(2-oxo-1,2,3,5-tetrahydroimidazo[2,1-b]quinoazolinyl)oxyalkylamides, compositions and the use thereof

ABSTRACT

Compounds according to the formula ##STR1## an optical isomer thereof, or a pharmaceutically acceptable acid addition salt thereof wherein: 
     n is an integer of 1 to 6; 
     R 1  is hydrogen or alkyl of 1 to 4 carbons; 
     R 2  is hydrogen or R 1  and R 2  are combined to form an oxo group; 
     R 3  is hydrogen, alkyl of 1 to 6 carbons, phenyl, benzyl, hydroxy lower alkyl or an aliphatic acylate thereof of 1 to 6 carbon atoms or an aryl acylate thereof of 7 to 12 carbon atoms, carbamoyl alkyl, carboxyalkyl, alkoxycarbonylalkyl of an α-amino acid side chain; 
     R 4  is hydrogen, alkyl of 1 to 6 carbons, benzyl, or hydroxy lower alkyl; 
     Y is hydrogen, alkyl of 1 to 4 carbon atoms, halo or lower alkoxy; 
     A is NR 5  R 6  wherein R 5  and R 6  are independently selected from the group consisting of: hydrogen; alkyl of 1 to 6 carbon atoms; hydroxyalkyl of 1 to 6 carbon atoms or an aliphatic acylate thereof of 1 to 6 carbon atoms or an aryl acrylate thereof of 7 to 12 carbon atoms; cycloalkyl of 3 to 8 carbon atoms or cycloalkyl lower alkyl of 4 to 12 carbon atoms wherein the cycloalkyl ring is unsubstituted or substituted with a lower alkyl, lower alkoxy, --OH, --OCOR 7 , halo, --NH 2 , --N(R 7 ) 2 , --NHCOR 7 , --COOH, or --COO(R 7 ) group wherein R 5  is lower alkyl; and phenyl or phenyl lower alkyl wherein phenyl is unsubstituted or substituted with at least one lower alkyl, halo or lower alkoxy group or an --NH 2 , --N(R 7 ) 2 , --NHCOR 7 , --COOH, or --COOR 7  group wherein R 7  is lower alkyl; or wherein R 5  and R 6  are combined to form a compound selected from the group consisting of: morpholinyl; piperidinyl; perhexylenyl; N-loweralkylpiperazinyl; pyrrolidinyl; tetrahydroquinolinyl; tetrahydroisoquinolinyl; (±)-decahydroquinolinyl and indolinyl. These compounds are cyclic AMP phosphodiesterase inhibitors useful as antithrombotic agents and the like in mammals. The compounds also have inotropic and anti-metastatic activities.

BACKGROUND OF THE INVENTION

This patent application is a continuation-in-part of U.S. Pat. No.4,551,459, issued Nov. 5, 1985 (filed Apr. 13, 1984 as U.S. Ser. No.06/599,858), which in turn is a continuation-in-part of U.S. Pat. No.4,490,371, issued Dec. 25, 1984 (filed Feb. 16, 1983 as U.S. Ser. No.06/467,125).

FIELD OF THE INVENTION

This invention relates to novel substituted1,2,3,5-tetrahydroimidazo[2,1-b]quinazolines which possessphosphodiesterase inhibiting properties, inotropic and anti-metastaticactivities. More specifically the compounds of interest are(2-oxo-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolinyl)oxyalkylamides andtheir pharmaceutically acceptable acid addition salts.

RELATED ART

Publication of possible interest herein are: F. Kienzie, et al, Eur. J.Med., 1982-17, No. 6d, pp 547-556 disclosing1,5-dihydroimidazoquinazolinones as blood platelet aggregationinhibitors; Japanese patent No. 54-163825; and U.S. Pat. No. 3,932,407.These references are relevant primarily for their disclosure ofsimilarly acting compounds, not because the compounds therein arestructural analogues to the compounds herein.

SUMMARY OF THE INVENTION

In a first aspect, this invention relates to compounds of the formula##STR2## an optical isomer thereof, or a pharmaceutically acceptableacid addition salt thereof wherein

n is an integer of 1 to 6;

R₁ is hydrogen or alkyl of 1 to 4 carbons;

R₂ is hydrogen or R₁ and R₂ are combined to form an oxo group;

R₃ is hydrogen, alkyl of 1 to 6 carbons, phenyl, benzyl, hydroxy loweralkyl or an aliphatic acylate thereof of 1 to 6 carbon atoms or an arylacylate thereof of 7 to 12 carbon atoms, carbamoyl alkyl, carboxyalkyl,alkoxycarbonylalkyl or an α-amino acid side chain;

R₄ is hydrogen, alkyl of 1 to 6 carbons, benzyl, or hydroxy lower alkyl;

Y is hydrogen, alkyl or 1 to 4 carbon atoms, halo or lower alkoxy;

A is NR₅ R₆ wherein R₅ and R₆ are independently selected from the groupconsisting of: hydrogen; alkyl of 1 to 6 carbon atoms; hydroxyalkyl of 1to 6 carbon atoms or an aliphatic acylate thereof of 1 to 6 carbon atomsor an aryl acylate thereof of 7 to 12 carbon atoms; cycloalkyl of 3 to 8carbon atoms or cycloalkyl lower alkyl of 4 to 12 carbonn atoms whereinthe cycloalkyl ring is unsubstituted or substituted with a lower alkyl,lower alkoxy, --OH, --OCOR₇, halo, --NH₂, --N(R₇)₂, --NHCOR₇, --COOH, or--COO(R₇) group wherein R₅ is lower alkyl; and phenyl or phenyl loweralkyl wherein phenyl is unsubstituted or substituted with at least onelower alkyl, halo or lower alkoxy group or an --NH₂, --N(R₇)₂, --NHCOR₇,--COOH, or --COOR₇ group wherein R₇ is lower alkyl; or wherein R₅ and R₆are combined to form a compound selected from the group consisting of:morpholinyl; piperidinyl; perhexylenyl; N-loweralkylpiperazinyl;pyrrolidinyl; tetrahydroquinolinyl; tetrahydroisoquinolinyl;(±)-decahydroquinolinyl and indolinyl.

In a second aspect, this invention relates to pharmaceuticallyacceptable compositions of one or more compounds according to Formula Iwherein said compounds are combined with at least one pharmaceuticallyacceptable excipient.

In yet another aspect, this invention relates to a method for inhibiting3',5'-cyclic AMP phosphodiesterase activity in a mammal, particularly, ahuman.

In yet another aspect, this invention relates to a method of treatingheart failure by stimulating suppressed heart activity which occursduring heart failure.

In yet another aspect, this invention relates to a method of inhibitingtumor growth.

The above three methods comprise administering a therapeuticallyeffective amount of a compound of this invention alone or in admixturewith a pharmaceutically acceptable excipient.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS OF THE INVENTIONUtility

The compounds of this invention are potent inhibitors of human plateletcyclic AMP phosphodiesterase activity. As a consequence, these compoundsinhibit the ADP-induced aggregation of human platelets. Thus, thesecompounds are useful in the prevention or treatment of a variety ofconditions related to platelet aggregation and thrombosis, for example,intravascular thrombosis, prevention of coronary thrombosis, preventionof transient ischemic episodes and prevention of platelet thrombosis andthe prevention of thrombosis, thrombocytopenia or platelet activationassociated with the use of prosthethic devices (artificial heart valves,etc.).

Cyclic AMP is known to regulate the activity of numerous enzymes andmediates the action of several hormones. Studies have demonstrated thata deficiency in cyclic AMP or an increase in the activity of a highaffinity cyclic AMP phosphodiesterase is associated with a variety ofdisease states. As inhibitors of 3',5'-cyclic AMP phosphodiesterase,compounds of this type are useful in the treatment or prevention ofhypertension, asthma, diabetes, obesity, immune disfunctions, psoriasis,inflammation, cardiovascular disease, tumor metastasis, cancer andhyperthyroidism. A more complete description of the various prophylacticand therapeutic activities of cyclic AMP phosphodiesterase inhibitingcompounds can be found in the following references: Amer, S. M., "CyclicNucleotides As Targets For Drug Design," Advances in Drug Research, Vol.12, 1977, Acedamic Press, London, pp 1-38; Weinryh, I. et al, J. Pharm.Sci., pp 1556-1567, (1972); Amer, S. M. & W. E. Kreighbaum, J. Pharm.Sci., V 64, pp 1-37, (1975); and Harris, D. N., et al, Enzyme InhibitorsAs Drugs, McMillan & Co., Ed-M. Sandler, pp 127-146, (1980).

The compounds of the present invention also have inotropic activity.They can strengthen myocardial contraction force by which the heartventricles can pump the blood into the periphery. Consequently, thesecompounds also are useful in treating myocardial failure.

Definitions

The compounds of the present invention are numbered as follows: ##STR3##

For the purpose of this disclosure, the compounds of the presentinvention are represented as having the single structural formulationrepresented by Formula I. However, when R₄ is hydrogen, compounds ofFormula I can exist in several possible tautomeric forms established bythe following core structures: ##STR4## All tautomers are part of thepresent invention.

The compounds of this invention may be prepared as structural isomerswherein the oxyalkylamide side chain is substituted on the benzene ringat any of the four different available positions. This fact isgraphically represented in the generic formula by the drawing of theline into the benzene ring without it being directed to a particularcarbon. In addition, the Y substituent or substituents may be present atany of one or more of the remaining ring positions as indicated byFormula I.

Also within the scope of this invention are the optical isomers of thosecompounds having an asymmetric center, such as when positions 3 and/or 4of the 1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-2-one structure aresubstituted with a substituent other than hydrogen. In addition A, maybe a substituent which has optical activity such as when A is a cycliccompound, for example, (+)- or (-)-decahydroquinolinyl.

Accordingly, the compounds of the present invention may be preparedeither in optically active form or as racemic mixtures. Unless otherwisespecified, where appropriate, products of the various synthetic stepsdescribed herein will be a racemic mixture. However, the scope of thesubject invention herein is not limited to the racemic mixture, but isto encompass the separated individual optical isomers of the disclosedcompounds.

If desired, the compounds herein may be resolved into their opticalantipodes by conventional resolution means, for example, by separation(e.g. fractional crystallization) of the diastereomeric salts formed bythe reaction of these compounds with optically active acids. Exemplaryof such optically active acids are the optically active forms ofcamphor-10-sulfonic acid, 2-bromo-camphor-α-sulfonic acid, camphoricacid, menthoxyacetic acid, tartaric acid, malic acid, diacetyltartaricacid, pyrrolidine-5-carboxylic acid and the like. The separated purediastereomeric salts may then be cleaved by standard means to afford therespective optical isomers.

For the purpose of this invention, the following phrases should beunderstood to have the recited meaning.

When reference is made to "alkyl of 1 to 6 carbon atoms" it is meantthat there is a branched or unbranched saturated hydrocarbon chaincontaining, in total, that number of carbon atoms. The phrase refersspecifically to such substituents as, for example, methyl, ethyl,n-propyl, i-propyl, n-butyl, tert-butyl, n-pentyl, n-hexyl and the like.The terms "alkyl of 1 to 4 carbon atoms" and "lower alkyl" are usedinterchangeably and mean methyl, ethyl, n-propyl, i-propyl, n-butyl,t-butyl and the like. When the term "alkyl" or prefix "alk" (such as inalkoxy) is used without qualification (such as the term "lower"), abranched or unbranched saturated hydrocarbon chain having from 1 to 12carbon atoms is contemplated.

"Lower alkoxy" means the group --OR wherein R is lower alkyl as definedin the foregoing paragraph.

When it is recited that R₁ and R₂ can be combined to form an oxo group,it is meant that at position 5, as numbered above, the carbon has adouble bond to an oxygen atom.

An "hydroxyalkyl" substituent is comprised of 1 to 6 carbon atoms,carbon, hydrogen and one oxygen atom, i.e. an alcohol wherein oneterminal carbon atom is substituted on the amide nitrogen and thehydroxyl group is substituted on another carbon, preferably theω-carbon. Herein the alkyl chain may be straight or branched, preferablystraight, is fully saturated and, except for the hydroxyl group, has noother substitution. Examples of hydroxyalkyl substituents are2-hydroxyethyl, 3-hydroxypropyl, 4-hydroxybutyl, 5-hydroxypentyl and6-hydroxyhexyl. This is not an exhaustive list of hydroxyalkylsubstituents which can be prepared or which can be used in thisinvention. It is merely intended to exemplify and identify that which isbeing referred to by the aforementioned phrase.

In the instance where the nitrogen in the amide-forming group and/or R₃is substituted with an hydroxyalkyl substituent, the hydroxy function(s)can be converted to an ester by reaction with a carboxylic acid. Such anacid may be any unbranched or branched aliphatic acid having 1 to 6carbon atoms such as, for example, formic acid, acetic acid, propionicacid, butyric acid, pentanoic acid, hexanoic acid or an isomer of theseacids which has up to 6 carbon atoms and is fully saturated. Theseesters are referred to herein as "aliphatic acylates of 1 to 6 carbonatoms." In addition, the carboxylic acid may be an aryl acid,exemplified by benzoic acid and having up to 7 to 12 carbon atoms.Representative radicals are, in addition to benzoic acid, phenylaceticacid, 3-phenylpropionic acid, 4-phenylbutyric acid, 6-phenylhexanoicacid and the like. Such acids serve to define and exemplify the term,directed to the ester product of the reaction, "aryl acylates of 7 to 12carbon atoms."

The term, "α-amino acid side chains," is meant to include amino acidside chains on naturally occurring amino acids and on commerciallyavailable synthetic amino acids, and amino acid side chains which can besynthesized or otherwise obtained by one of ordinary skill in the art oforganic chemistry; where in each instance the amine group and the sidechain are both attached to the α-carbon. Examples include amino acidside chains such as those found on cysteine, tyrosine, histidine,arginine, proline, phenylalanine, methionine, etc.

The phrase "unsubstituted or substituted" is used herein in conjunctionwith cycloalkyl and aryl substituents to indicate the ring may be haveon it only hydrogen or, alternatively, may be substituted with one ormore of the enumerated radicals as specifically indicated.

"Cycloalkyl of 3 to 8 carbon atoms" refers to a saturated aliphatic ringwhich contains 3 to 8 carbon atoms and which is substituted directlyonto the nitrogen without any intervening methylene groups. Suchradicals are, for example, cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, cycloheptyl and cyclooctyl.

When reference is made to "cycloaklyl lower alkyl of 4 to 12 carbonatoms," it is meant that the substituents denoted as cycloalkyl of 3 to8 carbon atoms in the preceding paragraph are attached to the nitrogenof the amide-forming group by means of a saturated branched orunbranched carbon chain which may have 1 to 4 carbon atoms. Suchsubstituents are, for example, cyclobutylmethyl, 4-cyclobutylbutyl,cyclopentylmethyl, 4-cyclopentylbutyl, cyclohexylmethyl,4-cyclohexylbutyl, cycloheptylmethyl and 4-cycloheptylbutyl, to name afew examples.

In addition, the cycloalkyl or cycloalkyl lower alkyl radicals recitedin the two foregoing paragraphs may be substituted with a radical chosenfrom the group consisting of lower alkyl, lower alkoxy, --OH, --OCOR₇,halo, --NH₂, --N(R₇)₂, --NHCOR₇, --COOH, and --COO(R₇) wherein R₇ islower alkyl.

"Phenyl lower alkyl" means a group having at least one and up to fourmethylene groups with an ω-phenyl group. In this instance the carbonchain is linear, not branched. The phenyl group may be unsubstituted,i.e., contain only hydrogen, or it may be substituted with up to 5substituents of a single functionality or a combination of the severalrecited substituents. Examples of unsubstituted phenyl lower alkyl arebenzyl, phenylethyl, phenylpropyl and phenylbutyl. Examples ofsubstituted phenyl lower alkyl are 4-halophenylalkyl,2,4-dihalophenylalkyl, 2,4,6-trihalophenylalkyl or2,3,4,5,6-pentahalo-phenylalkyl wherein halo is as defined below.

In addition, the phenyl group may be substituted with one or more loweralkyl groups such as methyl, ethyl, propyl or the like. One or morelower alkoxy groups may also be substituted on the phenyl ring. Inaddition, phenyl may be substituted with a radical chosen from the groupconsisting of --NH₂, --N(R₇)₂, --NHCOR₇, --COOH, and --COOR₇ wherein R₇is lower alkyl.

The term "halo" refers to fluoro, chloro and bromo and iodo.

The prefix D- and L- are used to describe the individual optical isomershaving an asymmetric center at the 3 or 5 position in the1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-2-one structure.

Perhexylenyl refers to the substituentdicyclohexyl-2-(2-piperidyl)ethane which is disclosed in British Pat.No. 1,025,578.

"Pharmaceutically acceptable acid addition salt" refers to those saltswhich retain the biological properties and efficacy of the free basesand which are not biologically or otherwise undesirable, formed withinorganic or organic acids. Inorganic acids which may be used are, forexample, hydrochloric acid, hydrobromic acid, sulfuric acid, nitricacid, phosphoric acid and the like. Exemplary organic acids are aceticacid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, malicacid, malonic acid, succinic acid, maleic acid, fumaric acid, tartaricacid, citric acid, benzoic acid, cinnamic acid, mandelic acid,methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid,salicylic acid and the like.

The compounds of Formula I in free base form may be converted to theacid addition salts by treating the base with a stoichiometric excess ofthe appropriate organic or inorganic acid. Typically, the free base isdissolved in a polar organic solvent such as ethanol or methanol, andthe acid added thereto. The temperature is maintained between about 0°C. and about 100° C. The resulting acid addition salt precipitatesspontaneously or may be brought out of solution with a less polarsolvent.

Administration and Dosage

Administration of the active compounds and salts thereof describedherein can be via any of the accepted modes of administration for agentswhich are cyclic AMP phosphodiesterase inhibitors. These methods includeoral, parenteral and otherwise systemic or aerosol forms.

Depending on the intended mode of administration, the compositions usedmay be in the form of solid, semi-solid or liquid dosage forms, such as,for example, tablets, suppositories, pills, capsules, powders, liquids,suspensions, or the like, preferably in unit dosage forms suitable forsingle administration of precise dosages. The compositions will includea conventional pharmaceutical carrier or excipient and an activecompound of Formula I or the pharmaceutically acceptable salts thereofand, in addition, may include other medicinal agents, pharmaceuticalagents, carriers, adjuvants, etc.

For oral administration, a pharmaceutically acceptable non-toxiccomposition is formed by the incorporation of any of the normallyemployed excipients, such as, for example pharmaceutical grades ofmannitol, lactose, starch, magnesium stearate, sodium saccharin, talcum,cellulose, glucose, sucrose, magnesium, carbonate, and the like. Suchcompositions take the form of solutions, suspensions, tablets, pills,capsules, powders, sustained release formulations and the like. Suchcompositions may contain between about 1% and about 99% activeingredient, but preferably contain between about 10% and about 50%active ingredient.

Parenteral administration is generally characterized by injection,either subcutaneously, intramuscularly or intravenously. Injectables canbe prepared in conventional forms, either as liquid solutions orsuspensions, solid forms suitable for solution or suspension in liquidprior to injection, or as emulsions. Suitable excipients are, forexample, water, saline, dextrose, glycerol, ethanol or the like. Inaddition, if desired, the pharmaceutical compositions to be administeredmay also contain minor amounts of non-toxic auxiliary substances such aswetting or emulsifying agents, pH buffering agents and the like, such asfor example, sodium acetate, sorbitan monolaurate, triethanolamineoleate, etc.

A more recently devised approach for parenteral administration employsthe implantation of a slow-release or sustained-release system, suchthat a constant level of dosage is maintained. See, e.g., U.S. Pat. Nos.3,710,795 and 3,773,919.

For systemic administration via suppository, traditional binders andcarriers include, e.g. polyalkylene glycols or triglycerides. Suchsuppositories may be formed from mixtures containing active ingredientin the range of about 0.5% to about 10%; and preferably in the range offrom about 1 to about 2%.

The amount of active compound administered will of course, be dependenton the subject being treated, the type and severity of the affliction,the manner of administration and the judgment of the prescribingphysician. In any case, a therapeutically effective amount of the drugeither alone or in combination with the various excipients listed aboveor otherwise known will be administered. For the purposes of thisinvention, "a therapeutically effective amount" refers to an amount inthe range of from about 0.1 to about 25 mg/kg of body weight, andpreferably from about 1 to about 10 mg/kg.

Preferred Embodiments

Preferred embodiments of the present invention are those compoundswherein n is 3 or 4; R₁, R₂ and R₃ are hydrogen; and R₄ is hydrogen ormethyl; or compounds wherein n is 3 or 4; R₁, R₂ and R₄ are hydrogen;and R₃ is alkyl of 1 to 6 carbon atoms, phenyl, benzyl, hydroxy loweralkyl and its aliphatic acylates of 1 to 6 carbons or aryl acylates of 7to 12 carbons or carbamoyl alkyl and optical isomers thereof.

More preferred embodiments are those compounds wherein n is 3 or 4; R₁,R₂ and R₃ are hydrogen; R₄ is hydrogen or methyl; and A is NR₅ R₆wherein the R₅ and R₆ substituents are independently selected from thegroup consisting of: alkyl of 1 to 6 carbon atoms; hydroxyalkyl of 1 to6 carbon atoms and its aliphatic acylates of 1 to 6 carbon atoms or arylacylates of 7 to 12 carbon atoms; cycloalkyl of 3 to 8 carbon atoms,cycloalkyl lower alkyl of 4 to 12 carbon atoms; phenyl or phenyl loweralkyl unsubstituted or substituted with 1 or more lower alkyl, halo orlower alkoxy groups; and optical isomers of the class of compounds. Anexample of the more preferred embodiments isN-cyclohexyl-N-(2-hydroxyethyl)-4-(2-oxo-1,2,3,5-tetrahydroimidazo[2,1b]quinazolin-7-yl)oxybutyramide.

Most preferred embodiments are those compounds wherein n is 3 or 4; R₁,R₂, R₃ and R₄ are hydrogen; and A is NR₅ R₆ wherein R₅ is alkyl of 1 to6 carbon atoms and R₆ cycloalkyl of 3 to 8 carbon atoms, and opticalisomers of the class of compounds. An example of the most preferredembodiments is:

N-cyclohexyl-N-methyl-4-(2-oxo-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-7-yl)oxybutyramide.

PREPARATION AND EXAMPLES

Compounds of the present invention can be made by several methods. Inthis disclosure, the process for preparing the claimed compounds beginswith a hydroxy-2-nitrobenzaldehyde which is reacted with anω-haloalkylester which serves to introduce the alkyl side chain onto thebenzene ring. The ester is then hydrolyzed, converted to the acidchloride and treated with the appropriate secondary amine to form theamide. If R₁ is to be a group other than hydrogen, that group isintroduced into the compound at this point by treating the amide with anappropriate Grignard reagent, which reacts with the aldehyde function,and then oxidizing the resulting alcohol to the ketone. The aldehyde orketone-containing amide is then treated with an α-amino acid or a saltthereof followed by a cyclization step employing a halo cyanogen andbase. Acid addition salts, etc are prepared from this base as needed ordesired.

Compounds of the present invention are prepared by the reaction sequenceoutlined in the following Reaction Schemes. ##STR5##

In Reaction Scheme A, the phenols of Formula (1) are known in the artand a number of them are readily available from commercial sources suchas Aldrich Chemical Co., Milwaukee, Wisc. They are converted to theω-(formylnitrophenyl)oxyalkyl esters by treating the phenol with anω-halo substituted alkyl ester of Formula (2). Generally, the reactionis carried out by mixing a mole equivalent of ω-haloalkylester, or up toa 20% excess thereof, with the parent phenol compound in a dry, dipolaraprotic solvent under an inert atmosphere. Solvents which may be used inthis reaction are, for example dimethylformamide, propylene carbonate,ethylene carbonate, diethylcarbonate, dimethylcarbonate, tetrahydrofuranand the like. Dimethylformamide is preferred. Preferably the reactionwill be carried out in a predried solvent and will be blanketed under adry inert atmosphere such as nitrogen.

A molar amount, but up to a 30% excess, of weak base is added to thesolution to effect the reaction. This weak base may be, for example, analkali metal carbonate or the like, preferably potassium carbonate. Thereaction requires between about 0.25 to about 2 hours at between roomtemperature and about 200° C. Preferably the reaction will be carriedout for about 1 hour at about 100° C.

Reaction products are isolated by conventionally known methodologies,preferably by solvent extraction into a compatible organic solvent. TheFormula (3) product may be further purified by distillation or otherappropriate means.

Conversion of the ester to its corresponding acid involvessaponification using well-known conditions and reagents. For example adilute solution of a strong base such as an alkali metal base is addedto an alcoholic solution of the ester in small portions and the reactionis allowed to run for about 10 to 60 minutes at a temperature betweenabout 0° C. and about 50° C. Alcohols which may be used as the solventfor this reaction are, for example, methanol, ethanol, propanol andisopropanol or the like, though it is preferable to use ethanol. Thebase may be, for example, sodium hydroxide, potassium hydroxide, orlithium hydroxide and the like, but it is preferable and most convenientto use sodium hydroxide. While the concentration of the added base mayrange between 1 and 6N it is preferable to begin with a 3N solution andadd it to the reaction mixture in a ratio of 1 part base for every 4parts of alcohol solution. Preferably the reaction is allowed to run forabout 30 minutes at room temperature after which the solution isneutralized with a concentrated solution of a strong acid such ashydrochloric acid or the like and the solvent evaporated. The product isthen further isolated by organic solvent extraction. Crystallizationfrom an appropriate solvent gives Formula (4) type compounds.

The conversion of Formula (4) acids to the acid chloride of Formula (5)is a known reaction. The reaction is carried out in a stirred solutionof acid in a non-polar, non-reactive solvent such as benzene or tolueneor the like to which has been added a small amount of a dipolar aproticsolvent such as dimethylformamide or the like by the addition of an acidhalide forming agent, preferably an acid chloride forming agent such asoxalyl chloride. The acid chloride forming reagent should be present inabout a 25 to 75% molar excess, preferably a 50% excess, in order toeffect a stoichiometric conversion of the acid to the acid halide.

The reaction is allowed to proceed at a temperature between about 0° andabout 45° C. for a time between about 15 minutes and about 2 hours.Preferable reaction conditions are about 20° C. for about 1 hour bywhich time the suspended acid should be completely dissolved.

Without further isolation, the solvent in which the acid chloride isdissolved in converted to a polar solvent by repetitive evaporation anddissolution of the acid chloride in the new polar solvent. This polarsolvent may be, for example, an ether such as tetrahydrofuran ordiethylether, preferably tetrahydrofuran and preferably dry.

Conversion of the acid chloride to the amide is carried out usingSchotten-Baumann reaction conditions which involves dropwise addition ofthe acid chloride to a well stirred, cooled mixture of a secondary amineand a weak base in an aqueous organic solvent wherein the organicsolvent is the same as that in which the acid chloride is dissolved. Thesecondary amine should be present in a molar excess of about 30% whilethe weak base is preferably present in a molar excess of about 35%.

Weak bases having utility for this reaction are the alkali metalcarbonates and the like, but particularly sodium carbonate. Duringaddition of the acid chloride to the amine, the reaction mixture shouldbe maintained at a temperature of about 0° C. When the addition of acidchloride is complete, the cooling bath may be removed and the reactionallowed to proceed at between about 10° C. and about 45° C., butpreferably at room temperature. The reaction is complete in about 15minutes to about 2 hours, most generally about 1 hour. Removal of theorganic solvent leaves an aqueous solution which is extracted to obtainthe amide. After appropriate washing of the organic layer, it isevaporated and the amide crystallized from an appropriate organicsolvent or chromatographically purified before crystallization.

An alternative method for preparing amides is to catalyze theirformation by means of 4-dimethylaminopyridine (DMAP) under anhydrousconditions and an inert atmosphere. The acid chloride, dissolved in adipolar aprotic solvent, such as ethyl ether, is added to a solution ofthe amine which is dissolved in a dipolar aprotic solvent containing anadditional base, for example a trialkylamine, or the like, butpreferably triethylamine. The amine will be present in a slight molarexcess relative to the acid chloride. The DMAP catalyst is present inthe mixture in an amount up to a 10% molar amount relative to the acidchloride. During addition of the acid chloride, the reaction mixture ismaintained at a temperature of between about -10° to +10° C. The inertatmosphere is preferably provided by the use of dry nitrogen.

When addition of the acid chloride is complete the solution is warmed tobetween about 15° C. and about 35° C., preferably room temperature, andthe reaction is allowed to proceed at that temperature for between about30 minutes and about 4 hours, preferably about 2 hours.

When R₁ is alkyl or phenyl, that moiety may be introduced into thecompound by reacting the Formula (6) aldehyde with a Grignard reagent oran alkyl lithium compound and then oxidizing the resulting secondaryalcohol to the ketone represented by Formula (8).

Alkyl magnesium halide reagents are readily available or may be easilyprepared from the alkyl halide and magnesium, a process well known inthe synthetic arts. Formation of the alcohol is effected by adding thealdehyde to a cooled ethereal solution of Grignard reagent wherein theGrignard reagent is present in a 10% molar excess relative to thealdehyde. After addition of the aldehyde is complete, the reaction isrefluxed for about 1 to about 4 hours, preferably about 2 hours.Degradation of the magnesium halide derivative to obtain the alcohol iscarried out by dropwise addition of a mineral acid, for example a 25%sulfuric acid solution. This solution is neutralized with a weak baseand the alcohol isolated in preparation for treatment with an oxidizingagent to regenerate the carbonyl group.

The oxidation of Formula (7) type compounds is carried out via somestrong oxidizing agent under selected conditions which minimize amideoxidation. There may be used, for example, a chromium trioxide-pyridinecomplex or the like. Preferably the reaction will be carried out underanhydrous conditions under an inert atmosphere and in a polar organicsolvent which is inert to the oxidizing reagent, such as a halogenatedhydrocarbon. Reaction temperatures will between about 0° C. to about100° C. for a period of about 1 to about 8 hours. A 10% molar excess ofoxidizing agent relative to the alcohol is sufficient to effect thedesired oxidation.

Herein a preferred oxidizing reagent is the Collins reagent [J. C.Collins, et al., Tetrahedron Letters, p 3363 (1968)] which employs achromium trioxide-pyridine complex in a halogenated hydrocarbon solventsystem. The reaction is carried out under anhydrous conditions in aninert atmosphere. The preferred organic solvents are for example,methylene chloride, carbon tetrachloride, ethylene chloride, or thelike. The inert atmosphere is maintained by the use of a dry inert gas,preferably dry nitrogen. Usually a temperature between about 0° to about50° C. for a period of about 0.5 to about 5 hours is generallysufficient to effect the reaction. Most preferably the reaction will becarried out in dry methylene chloride under a dry nitrogen atmospherefor about 1 hour at room temperature.

Formula (6) and Formula (8) compounds may then be converted to compoundsof Formula (9) by reacting the aldehyde or ketone with an α-amino acidester. For the purposes of this invention any lower alkyl ester of anaturally occurring α-amino acids or any synthetic α-amino acid estermay be used in the practice of this invention. Generally, the reactionis carried out at a temperature between about 0°-50° C., preferablyambient temperature. A time of between about 1 to about 8 hours issufficient to effect the reaction though about 3 to about 4 hours ispreferable. The reaction is generally carried out in a polar solventsuch as an alcohol, for example, methanol, ethanol, propanol, or thelike in which the aldehyde/ketone and the ester are soluble. It ispreferable to add a water-scavenging agent such as molecular sieves inorder to remove water generated during the reaction process.

Initially, a reaction mixture is prepared which contains the carbonylcompound (aldehyde (6) or ketone (8)), about a two-fold molar amount ofthe α-amino acid ester as an acid addition salt, and the waterscavenging agent. To this mixture is added a large molar excess of theα-aminocarboxylic acid ester, about 6 to 10-fold excess. The solution isgenerally maintained between about 10° to 30° C. during this additionprocess. After addition of the ester is complete, there is added acyanoborohydride reducing agent in a molar amount of about one-half thatof the carbonyl compound. The reaction is allowed to proceed at atemperature between about 10° to 30° C., preferably at room temperaturefor a period of between about 1 to about 6 hours, preferably about 3 toabout 4 hours.

While the reaction product may be isolated for characterization, etc.,that is not necessary. It is most convenient to simply removeprecipitated solids, i.e, the molecular sieves and borate salts, byfiltration, evaporate the solvent and to take up the residue in anorganic solvent. This solution may then be washed with a base and brineto remove impurities, after which the solvent is removed and theresulting residue used directly in the next reaction step.

Reduction of the nitro group is most conveniently carried out bycatalytic hydrogenation. This reaction may be accomplished byconventionally known means. As practiced herein, the residue from theprevious reaction step is dissolved in an appropriate solvent such as,for example, a simple alcohol such as methanol or ethanol. A transitionmetal catalyst which will selectively reduce the nitro group to theamine without affecting the amide or the phenyl ring is preferred. Apreferred catalyst is a palladium catalyst and most preferably it willbe palladium on carbon such as the readily available 10%palladium/carbon catalyst.

A small amount of the palladium/carbon catalyst, i.e., between about 0.5and about 1.5 grams, will generally be sufficient to effect thereduction. The alcoholic reaction mixture is placed under hydrogen atroom temperature and allowed to proceed till an equivalent of hydrogenhas been taken up. Isolation of the hydrogenation product is readilyaccomplished by filtration to remove the catalyst after which thereaction product may be used directly in the following step.

Cyclization of the amine is achieved by means of a cyanogen halide,preferably the bromide. A 5 to 10% molar excess of cyanogen halide isadded to the solution from the previous reaction. The resulting solutionis refluxed overnight, preferably about 16 hours.

The resulting reaction mixture is then treated with a solution of astrong base for about 0.5 to about 4 hours at a temperature betweenabout 0° C. and about 50° C. Bases which may be used to effect thisreaction are preferably alkali metal bases such as sodium hydroxide,potassium hydroxide and the like. They are used at a concentration ofbetween about 1 to 6N, preferably about 2N. A molar amount of baseequivalent to that of the cyanogen halide employed in the previous stepis employed in this final reaction step. Preferably the reaction will beallowed to proceed for about 2 hours at room temperature during whichtime the product generally will precipitate as a powder. The product,Formula I wherein R₄ is hydrogen, can be further isolated andcharacterized by filtration or centrifugation, followed by drying or byrecrystallization from an appropriate organic solvent.

Further transformation of compounds where R₄ is H to those where R₄ isalkyl, benzyl, etc., is accomplished by treating the former withalkylating agents and a strong base, such as potassium tert-butoxide orsodium hydride in a dipolar aprotic solvent such as dimethyl formamide.

Where A or R₃ in Formula I contains an hydroxylalkyl group, that groupcan be esterified by treating the compound with an acid anhydride inpyridine.

The optical isomers of Formula (I) wherein R₃ is a substituent otherthan hydrogen can be prepared following the same procedures as describedabove except while reacting with the carbonyl compound (6) or (8), anoptically active α-aminocarboxylic acid ester (NH₂ CHR₃ COOR₆) should beused.

The compounds of Formula I in free base form may be converted to theacid addition salts by treatment with a stoichiometric excess of theappropriate organic or inorganic acid. Typically, the free base isdissolved in a polar organic solvent such as ethanol or methanol, andthe acid added thereto. The temperature is maintained between about 0°C. and about 100° C. The resulting acid addition salt precipitatesspontaneously or may be brought out of solution with a less polarsolvent.

The acid addition salts of the compounds of Formula I may be decomposedto the corresponding free base by treatment with a stoichiometric excessof a suitable base, such as potassium carbonate or sodium hydroxide,typically in the presence of aqueous solvent, and at a temperature ofbetween about 0° C. and 100° C. The free base form is isolated byconventional means, such as extraction with an organic solvent.

Salts of the compounds of Formula I may be interchanged by takingadvantage of differential solubilities of the salts, volatilities oracidities of the acids, or by treating with the appropriately loaded ionexchange resin. For example, the interchange is effected by the reactionof a salt of the compounds of Formula I with a slight stoichiometricexcess of an acid of a lower pKa than the acid component of the startingsalt. This conversion is carried out at a temperature between about 0°C. and the boiling point of the solvent.

An alternative route for preparing the compounds of Formula (I) whereinR₁ and R₂ are combined to form an oxo group and R₃ and R₄ are hydrogenis exemplified by the following reaction scheme. ##STR6##

The compounds of Formula (6) are prepared as described above in ReactionScheme A.

The compounds of Formula (11) are prepared by oxidizing thecorresponding aldehydes with an oxidizing agent such as silver acetate,sodium chlorite-sulfamic acid, chromium trioxide-pyridine complexes oralkylammonium permanganates, for example. Usually the reaction will becarried out under an inert atmosphere in a dry, nitrogen-containingsolvent at a temperature between about 0° C. and about 50° C. for aperiod of about 15 minutes to about 3 hours. Preferably, the oxidationwill be effected by an alkylammonium permanganates such astetra-butylammonium permanganate in dry pyridine under a dry nitrogenblanket. The reaction is complete in about 1 hour at room temperature.

Reduction of the nitro group to obtain the anthranilic acid compounds ofFormula (12) is by catalytic hydrogenation. This reaction employs aheavy metal catalyst dispersed in a simple alcohol containing thenitroacid and put under hydrogen at room temperature until hydrogenuptake is complete. In this instance, it is preferable to add 10%palladium-on-carbon to an ethanolic solution of the nitroacid and placethe mixture under about 60 psi hydrogen overnight. Alternatively, thehydrogenation can be carried out with the addition of a mineral acidsuch as hydrogen chloride, which procedure gives the acid salt directlyas a hygroscopic solid.

The amines of Formula (12) are converted directly to Formula I compoundsby treating the acids, dissolved in a simple alcohol, with a 2-3 molarexcess of 2-methylthiohydantoin. Generally the reaction is carried outunder reflux for about 1 to about 6 hours. Preferably the reaction willbe carried out in ethanol under reflux for about 3 hours.

REACTION SCHEME C

Compounds of Formula I may also be prepared from the7-hydroxy-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-2-one or its 6, 8or 9-hydroxy analogs by the sequence of steps set out below. ##STR7##

The compounds of Formula 13 are prepared as described in U.S. Pat. No.3,932,407 which is incorporated herein by reference.

Alkylation of the hydroxy compounds is achieved by the use ofω-bromoalkanoates (10% molar excess) in a dipolar solvent suchdimethylformamide in the same manner described for the preparation ofFormula 3 compounds in reaction Scheme A. Ester hydrolysis, to giveFormula 14 compounds, is carried out in the same manner as describedhereinabove for the conversion of Formula 3 compounds to those ofFormula 4 in reaction Scheme A.

Amides are prepared directly from the acid by condensation means. Thereaction of the acid and an amide forming agent may be carried out in adipolar aprotic solvent such as dimethylformamide at a temperaturebetween about 0° to about 40° C. For example, first the acid and a 10%molar excess of 1-hydroxybenzotriazole is dissolved in the reactionmedium after which a dialkylcarbodiimide, preferablediisopropylcarbodiimide is added. After a period of about 0.25 to about2 hours, preferably about 1 hour, a solution of N-methylcyclohexylamine(20% molar excess) and N-methyl morpholine (20% molar excess) is added.Overnight stirring at about ambient temperature completes the reaction.

The unsubstituted or primary amides of Formula (I) can be prepared byreacting the ester compound (14) with ammonia or other appropriateprimary amines either by saturation of a gas or by using 5 equivalentsof a liquid in a polar solvent at a temperature of about 100° C. toabout 200° C., sometimes in a pressure vessel.

The following Preparations and Examples are set out to illustrate thereaction steps graphically recited above.

PREPARATION 1

The preparation of ω-((formyl-nitrophenyl)oxy)alkyl acid esters (seeFormula 3) is described herein.

To a solution of 5-hydroxy-2-nitrobenzaldehyde (84.0 g) and ethyl4-bromobutyrate (86 ml) in dry dimethylformamide (500 ml) blanketedunder dry nitrogen was added potassium carbonate (76.0 g). The reactionmixture was heated to 100° C. for 1 hour. This mixture was cooled, andthe solvent removed by evaporation to give a dark brown syrup. Thisresidue was partitioned between ethyl acetate and saturated sodiumcarbonate (500 ml each). The organic layer was washed with additionalsaturated sodium carbonate (3×500 ml), and with brine (2×500 ml), dried,filtered and evaporated to give a dark brown syrup. Kugelrohrdistillation (180° C., 0.2 mm) afforded ethyl4-((3-formyl-4-nitrophenyl)oxy)butyrate (95 g) as a bright yellow syrupwhich slowly darkened upon standing.

Using the above procedure, but substituting the appropriate aldehyde for5-hydroxy-2-nitrobenzaldehyde and alkyl ω-bromoalkylate for ethyl4-bromobutyrate there may be prepared, for example, the followingcompounds:

ethyl 4-(2-chloro-3-formyl-4-nitrophenyl)oxybutyrate;

ethyl 4-(3-formyl-4-nitro-5-chlorophenyl)oxybutyrate;

ethyl 4-(2-chloro-4-nitro-5-formylphenyl)oxybutyrate;

ethyl 4-(3-formyl-4-nitro-5-fluorophenyl)oxybutyrate;

ethyl 4-(2-fluoro-3-formyl-4-nitrophenyl)oxybutyrate;

ethyl 4-(2-methyl-3-formyl-4-nitrophenyl)oxybutyrate;

ethyl 4-(2-formyl-3-nitro-6-fluorophenyl)oxybutyrate;

ethyl 4-(2-formyl-3-nitro-chlorophenyl)oxybutyrate;

ethyl 4-(2-formyl-3-nitro-5-fluorophenyl)oxybutyrate;

ethyl 4-(2-formyl-3-nitrophenyl)oxybutyrate;

ethyl 4-(2-formyl-3-nitro-5-methylphenyl)oxybutyrate;

ethyl 4-(2-formyl-3-nitro-6-fluorophenyl)oxybutyrate;

ethyl 4-(2-nitro-3-formylphenyl)oxybutyrate;

ethyl 4-(2-nitro-3-formyl-5-methylphenyl)oxybutyrate;

ethyl 4-(3-nitro-4-formyl-6-fluorophenyl)oxybutyrate;

ethyl 4-(2-chloro-4-formyl-5-nitrophenyl)oxybutyrate;

ethyl 4-(3-nitro-4-formylphenyl)oxybutyrate;

ethyl 4-(3-nitro-4-formyl-5-methylphenyl)oxybutyrate;

ethyl 4-(2-nitro-3-formyl-6-fluorophenyl)oxybutyrate;

ethyl 4-(2-nitro-3-formyl-6-chlorophenyl)oxybutyrate;

ethyl 7-(3-formyl-4-nitrophenyl)oxyheptanoate;

ethyl 7-(2-chloro-3-formyl-4-nitrophenyl)heptanoate;

ethyl 7-(2-methyl-3-formyl-4-nitrophenyl)heptanoate;

ethyl 7-(3-formyl-4-nitro-5-chlorophenyl)heptanoate;

ethyl 7-(2-formyl-3-nitrophenyl)heptanoate;

ethyl 7-(2-formyl-3-nitro-4-fluorophenyl)heptanoate;

ethyl 7-(2-methyl-3-formyl-4-nitrophenyl)heptanoate;

ethyl 7-(2-formyl-3-nitro-5-chlorophenyl)heptanoate;

ethyl 7-(2-nitro-3-formylphenyl)heptanoate;

ethyl 7-(2-nitro-3-formyl-4-fluorophenyl)heptanoate;

ethyl 7-(2-nitro-3-formyl-6-chlorophenyl)heptanoate;

ethyl 7-(2-nitro-3-formyl-5-methylphenyl)heptanoate;

ethyl 7-(3-nitro-4-formylphenyl)heptanoate;

ethyl 7-(3-nitro-4-formyl-5-methylphenyl)heptanoate;

ethyl 5-(2-formyl-3-nitrophenyl)oxypentanoate;

ethyl 5-(2-formyl-3-nitro-4-chlorophenyl)oxypentanoate;

ethyl 5-(2-formyl-3-nitro-4-methylphenyl)oxypentanoate;

ethyl 5-(2-formyl-3-nitro-6-methylphenyl)oxypentanoate;

ethyl 5-(3-formyl-4-nitro-5-chlorophenyl)oxypentanoate;

ethyl 5-(2-chloro-3-formyl-4-nitrophenyl)oxypentanoate;

ethyl 5-(3-formyl-4-nitrophenyl)oxypentanoate;

ethyl 5-(3-nitro-4-formylphenyl)oxypentanoate;

ethyl 5-(3-nitro-4-formyl-5-methylphenyl)oxypentanoate;

ethyl 5-(3-nitro-4-formyl-6-chlorophenyl)oxypentanoate;

ethyl 5-(3-formyl-4-nitro-6-chlorophenyl)oxypentanoate;

ethyl 5-(2-nitro-3-formylphenyl)oxypentanoate;

ethyl 5-(2-nitro-3-formyl-4-methylphenyl)oxypentanoate;

ethyl 5-(2-nitro-3-formyl-6-chlorophenyl)oxypentanoate;

ethyl 6-(2-formyl-3-nitrophenyl)oxyhexanoate;

ethyl 6-(2-formyl-3-nitro-4-chlorophenyl)oxyhexanoate;

ethyl 6-(2-formyl-3-nitro-6-chlorophenyl)oxyhexanoate;

ethyl 6-(3-formyl-4-nitrophenyl)oxyhexanoate;

ethyl 6-(3-formyl-4-nitro-6-chlorophenyl)oxyhexanoate;

ethyl 6-(3-formyl-4-nitro-5-methylphenyl)oxyhexanoate;

ethyl 6-(2-nitro-3-formylphenyl)oxyhexanoate;

ethyl 6-(2-nitro-3-formyl-6-fluorophenyl)oxyhexanoate;

ethyl 6-(2-nitro-3-formyl-5-methylphenyl)oxyhexanoate;

ethyl 6-(3-nitro-4-formylphenyl)oxyhexanoate;

ethyl 6-(3-nitro-4-formyl-6-methylphenyl)oxyhexanoate;

ethyl 6-(3-nitro-4-formyl-5-chlorophenyl)oxyhexanoate;

ethyl 2-(2-chloro-3-formyl-4-nitrophenyl)oxyacetate;

ethyl 2-(3-formyl-4-nitrophenyl)oxyacetate;

ethyl 2-(3-formyl-4-nitro-5-chlorophenyl)oxyacetate;

ethyl 2-(2-chloro-4-nitro-5-formylphenyl)oxyacetate; and

ethyl 2-(3-formyl-4-nitro-5-fluorophenyl)oxyacetate.

PREPARATION 2

Ester hydrolysis to give the acids of Formula 4 is described herein.

To a solution of ethyl 4-(3-formyl-4-nitrophenyl)oxybutyrate (65 g) inethanol (400 ml) was added 3N NaOH (100 ml) in small portions. After 30minutes at room temperature the reaction mixture was acidified withconcentrated HCl and the ethanol evaporated. The aqueous residue wasextracted with ethyl acetate (4×200 ml). The combined organic layerswere washed with brine (2×200 ml), dried over Na₂ SO₄, filtered andevaporated to give a light yellow solid. Trituration with ether afforded4-(3-formyl-4-nitrophenyl)oxybutyric acid (55 g), m.p. 109°-110° C.

Following the above procedure, the esters prepared as per Preparation 1are converted to the corresponding acid.

PREPARATION 3

Conversion of the acids of Formula 4 in Reaction Scheme A to the acidhalide, preferably the chloride, preparatory to forming the amidecompounds of Formula 6 was carried out as follows:

To a stirred suspension of 4-(3-formyl-4-nitrophenyl)oxybutyric acid(12.65 g) in benzene (50 ml) and dimethylformamide (0.5 ml) was addedoxalyl chloride (4.40 ml) in small portions. When all the acid had beendissolved, the mixture was stirred for an additional 30 minutes.Evaporation of the solvent gave a thick syrup which was redissolved indry tetrahydrofuran (50 ml) and reevaporated twice. The final residue ofcrude acid chloride was dissolved in tetrahydrofuran (50 ml) and usedwithout further purification in the next reaction step.

Proceeding in a similar manner, the acids prepared as per Preparation 2are converted to the corresponding acid chloride.

PREPARATION 4

Preparation of the amides represented by Formula 6 is carried out byeither of the following two steps.

A. Into a well-stirred solution of N-methyl-N-cyclohexylamine (29.5 ml)and sodium carbonate (28.8 g) in tetrahydrofuran (250 ml) and water (500ml) cooled to 0° C. in an ice bath was added the tetrahydrofuransolution of the 4-(3-formyl-5-nitrophenyl)oxybutyric acid chloride fromPreparation 3 dropwise. When addition of the acid chloride wascompleted, the cooling bath was removed and the mixture allowed to stirat room temperature for 1 hour. Most of the tetrahydrofuran was removedby evaporation and the aqueous residue partitioned between ethyl acetateand saturated sodium carbonate (500 ml each). The combined organiclayers were washed with additional saturated sodium carbonate (2×20 ml),water (1×100 ml), 1M HCl (2×200 ml) and with brine (2×200 ml) and driedwith sodium sulfate. The ethyl acetate was evaporated to give a residuewhich was crystallized from ethyl acetate to giveN-cyclohexyl-N-methyl-4-(3-formyl-4-nitrophenyl)oxybutyramide, (m.p.98°-100° C.). Alternatively, the extraction residue was chromatographedon silica gel (10% ethyl acetate in dichloromethane as eluant.

B. A tetrahydrofuran solution of 4-(3-formyl-4-nitrophenyl)oxybutyricacid chloride was added dropwise to a solution ofN-cyclohexyl-N-methylamine (60 mmol), triethylamine (9.0 ml) and4-dimethylaminopyridine (0.6 g) in dry tetrahydrofuran (100 ml)blanketed under nitrogen and cooled to 0° C. by an ice bath. Whenaddition of the acid chloride was complete the reaction was stirred atroom temperature for 2 hours. After removal of the tetrahydrofuran, theresidue was partitioned between ethyl acetate and 1M HCl (300 ml each).The organic layer was then washed with 1M HCl (2×100 ml), saturatedsodium carbonate (3×100 ml) and brine (2×100 ml), dried over sodiumsulfate filtered and the ethyl acetate flash evaporated. Purification ofthe residue was carried out as in method A above.

Using either of these procedures and substituting the appropriatesecondary amine and acid chloride for those described, there may beprepared the following representative compounds:

N-cyclohexyl-N-hydroxyethyl-4-(3-formyl-4-nitrophenyl)oxybutyramide,m.p. 108°-110° C.;

N-cyclohexylmethyl-N-hydroxyethyl-4-(3-formyl-4-nitrophenyl)oxybutyramide;

N-hexyl-N-methyl-4-(3-formyl-4-nitrophenyl)oxybutyramide;

N,N-dimethyl-4-(3-formyl-4-nitrophenyl)oxybutyramide;

N-ethyl-N-methyl-4-(3-formyl-4-nitrophenyl)oxybutyramide;

N-pentyl-N-methyl-4-(3-formyl-4-nitrophenyl)oxybutyramide;

N-hexyl-N-hydroxyethyl4-(3-formyl-4-nitrophenyl)oxybutyramide;

N,N-dihexyl-4-(3-formyl-4-nitrophenyl)oxybutyramide;

N,N-dipentyl-4-(3-formyl-4-nitrophenyl)oxybutyramide;

N-cyclohexyl-N-6-hydroxyhexyl-4-(3-formyl-4-nitrophenyl)oxybutyramide;

N-cyclohexyl-N-n-hexyl-4-(3-formyl-4-nitrophenyl)oxybutyramide;

N-cyclopentyl-N-methyl-4-(3-formyl-4-nitrophenyl)oxybutyramide;

N-cyclopropylmethyl-N-methyl-4-(3-formyl-4-nitrophenyl)oxybutyramide;

N-cycloheptyl-N-methyl-4-(3-formyl-4-nitrophenyl)oxybutyramide;

N-cyclopentylbutyl-N-methyl-4-(3-formyl-4-nitrophenyl)oxybutyramide;

N-cyclopentylmethyl-N-methyl-4-(3-formyl-4-nitrophenyl)oxybutyramide;

N-cyclopentyl-N-butyl-4-(3-formyl-4-nitrophenyl)oxybutyramide;

N-cyclopentyl-N-hydroxyethyl-4-(3-formyl-4-nitrophenyl)oxybutyramide;

N-cyclopentylmethyl-N-hydroxyethyl-4-(3-formyl-4-nitrophenyl)oxybutyramide;

N-cyclopentylbutyl-N-hydroxyethyl-4-(3-formyl-4-nitrophenyl)oxybutyramide;

N,N-dicyclohexyl-4-(3-formyl-4-nitrophenyl)oxybutyramide, m.p. 107°-108°C.;

N-cyclohexyl-N-4-hydroxy-n-butyl-4-(3-formyl-4-nitro-5-methylphenyl)oxybutyramide;

N-phenyl-N-methyl-4-(3-formyl-4-nitrophenyl)oxybutyramide, m.p. 72°-73°C.;

N-phenyl-N-hexyl-4-(3-formyl-4-nitrophenyl)oxybutyramide;

N-phenyl-N-hydroxymethyl-4-(3-formyl-4-nitrophenyl)oxybutyramide;

N-phenyl-N-6-hydroxyhexyl-4-(3-formyl-4-nitrophenyl)oxybutyramide;

N-cyclohexyl-N-n-butyl-4-(3-formyl-4-nitrophenyl)oxybutyramide;

N-benzyl-N-methyl-4-(3-formyl-4-nitrophenyl)oxybutyramide, syrup;

N,N-dibenzyl-4-(3-formyl-4-nitrophenyl)oxybutyramide, m.p. 76°-77° C.;

N-diphenylmethyl-N-methyl-4-(3-formyl-4-nitrophenyl)oxybutyramide, m.p.117°-118° C.;

morpholinyl-4-(3-formyl-4-nitrophenyl)oxybutyramide, m.p. 106°-107° C.;

piperidinyl-4-(3-formyl-4-nitrophenyl)oxybutyramide, m.p. 98°-99° C.;

pyrrolidinyl-4-(3-formyl-4-nitrophenyl)oxybutyramide, m.p. 82°-83° C.;

N-methylpiperazinyl-4-(3-formyl-4-nitrophenyl)oxybutyramide;

tetrahydroquinolinyl-4-(3-formyl-4-nitrophenyl)oxybutyramide, m.p.95°-96° C.;

tetrahydroisoquinolinyl-4-(3-formyl-4-nitrophenyl)oxybutyramide, m.p.99°-100° C.;

indolinyl-4-(3-formyl-4-nitrophenyl)oxybutyramide, m.p. 155°-156° C.;

(±)-decahydroquinolinyl-4-(3-formyl-4-nitrophenyl)oxybutyramide;

N-cyclohexyl-N-hydroxyethyl-4-(2-formyl-3-nitro-4-chlolophenyl)oxybutyramide;

N-cyclohexyl-N-methyl-4-(2-formyl-3-nitrophenyl)oxybutyramide;

N-cyclohexyl-N-4-hydroxy-n-butyl-4-(2-formyl-3-nitrophenyl)oxybutyramide;

N-cyclohexyl-N-n-hexyl-4-(2-formyl-3-nitrophenyl)oxybutyramide;

N-phenyl-N-methyl-4-(2-formyl-3-nitrophenyl)oxybutyramide;

N-benzyl-N-methyl-4-(2-formyl-3-nitrophenyl)oxybutyramide;

N,N-dibenzyl-4-(2-formyl-3-nitrophenyl)oxybutyramide;

N,N-dicychlohexyl-4-(2-formyl-3-nitrophenyl)oxybutyramide;

(±)-decahydroquinolinyl-4-(2-formyl-3-nitro-4-chlorophenyl)oxybutyramide;

N-cyclohexyl-N-hydroxyethyl-4-(2-nitro-3-formylphenyl)oxybutyramide;

N-phenyl-N-methyl-4-(2-nitro-3-formylphenyl)oxybutyramide;

N-cyclohexyl-N-methyl-4-(2-nitro-3-formylphenyl)oxybutyramide;

N-benzyl-N-methyl-4-(2-nitro-3-formylphenyl)oxybutyramide;

N,N-dibenzyl-4-(2-nitro-3-formylphenyl)oxybutyramide;

N,N-dicyclohexyl-4-(2-nitro-3-formylphenyl)oxybutyramide;

(±)-decahydroquinolinyl-4-(2-nitro-3-formylphenyl)oxybutyramide;

N-diphenylmethyl-N-methyl-4-(2-nitro-3-formylphenyl)oxybutyramide;

N-cyclohexyl-N-hydroxyethyl-4-(3-nitro-4-formylphenyl)oxybutyramide;

N-cyclohexyl-N-methyl-4-(3-nitro-4-formylphenyl)oxybutyramide;

N-phenyl-N-methyl-4-(3-nitro-4-formylphenyl)oxybutyramide;

N-benzyl-N-methyl-4-(3-nitro-4-formylphenyl)oxybutyramide;

N,N-dibenzyl-4-(3-nitro-4-formylphenyl)oxybutyramide;

N,N-dicychlohexyl-4-(3-nitro-4-formylphenyl)oxybutyramide;

(±)-decahydroquinolinyl-4-(3-nitro-4-formylphenyl)oxybutyramide;

N-diphenylmethyl-N-methyl-4-(3-nitro-4-formylphenyl)oxybutyramide;

N-cyclohexyl-N-hydroxyethyl-7-(3-formyl-4-nitrophenyl)oxyheptanamide;

N-cyclohexyl-N-hydroxymethyl-7-(3-formyl-4-nitrophenyl)oxyheptanamide

N-cyclohexyl-N-n-hexyl-(3-formyl-4-nitrophenyl)-7-oxyheptanamide;

N-benzyl-N-methyl-7-(3-formyl-4-nitrophenyl)oxyheptanamide;

N,N-dibenzyl-7-(3-formyl-4-nitrophenyl)oxyheptanamide;

N-diphenylmethyl-N-methyl-7-(3-formyl-4-nitrophenyl)oxyheptanamide;

(±)-decahydroquinolinyl-7-(3-formyl-4-nitrophenyl)oxyheptanamide;

N-cyclohexyl-N-hydroxyethyl-7-(2-formyl-3-nitro-4-chlolophenyl)oxyheptanamide;

N-cyclohexyl-N-methyl-7-(2-formyl-3-nitrophenyl)oxyheptanamide;

N-cyclohexyl-N-4-hydroxy-n-butyl-7-(2-formyl-3-nitrophenyl)oxyheptanamide;

N-phenyl-N-methyl-7-(2-formyl-3-nitrophenyl)oxyheptanamide;

N-benzyl-N-methyl-7-(2-formyl-3-nitrophenyl)oxyheptanamide;

N-cyclohexyl-N-hydroxyethyl-7-(2-nitro-3-formylphenyl)oxyheptanamide;

N-phenyl-N-methyl-7-(2-nitro-3-formylphenyl)oxyheptanamide;

N-cyclohexyl-N-methyl-7-(2-nitro-3-formylphenyl)oxyheptanamide;

N,N-dicychlohexyl-7-(2-nitro-3-formylphenyl)oxyheptanamide;

N-cyclohexyl-N-hydroxyethyl-7-(3-nitro-4-formyl)oxyphenyl)oxyheptanamide;

N-cyclohexyl-N-butyl-7-(3-nitro-4-formylphenyl)oxyheptanamide;

N-benzyl-N-methyl-7-(3-nitro-4-formylphenyl)oxyheptanamide;

N,N-dibenzyl-7-(3-nitro-4-formylphenyl)oxyheptanamide;

(±)-decahydroquinolinyl-7-(3-nitro-4-formylphenyl)oxyheptanamide;

N-cyclohexyl-N-hydroxyethyl-5-(3-formyl-4-nitrophenyl)oxypentanamide;

N-cyclohexyl-N-hydroxymethyl-5-(3-formyl-4-nitrophenyl)oxypentanamide;

N-cyclohexyl-N-methyl-5-(3-formyl-4-nitrophenyl)oxypentanamide;

N-cyclohexyl-N-hexyl-5-(3-formyl-4-nitrophenyl)oxypentanamide;

N-cyclopentyl-N-6-hydroxyhexyl-5-(3-formyl-4-nitrophenyl)oxypentanamide;

N-cyclopentyl-N-hydroxypropyl-5-(3-formyl-4-nitrophenyl)oxypentanamide;

N-cyclopentyl-N-methyl-5-(3-formyl-4-nitrophenyl)oxypentanamide;

N-cyclopentyl-N-hexyl-5-(3-formyl-4-nitrophenyl)oxypentanamide;

N-hexyl-N-methyl-5-(3-formyl-4-nitrophenyl)oxypentanamide;

N-methyl-N-methyl-5-(3-formyl-4-nitrophenyl)oxypentanamide;

N,N-dihexyl-5-(3-formyl-4-nitrophenyl)oxypentanamide;

N-phenyl-N-methyl-5-(3-formyl-4-nitrophenyl)oxypentanamide;

N-benzyl-N-methyl-5-(3-formyl-4-nitrophenyl)oxypentanamide;

N-cyclohexyl-N-hydroxyethyl-5-(2-formyl-3-nitro-4-chlolophenyl)oxypentanamide;

N-cyclohexyl-N-methyl-5-(2-formyl-3-nitrophenyl)oxypentanamide;

N-cyclohexyl-N-butyl-5-(2-formyl-3-nitro-phenyl)oxypentanamide;

N-cyclohexyl-N-hydroxyethyl-5-(2-nitro-3-formylphenyl)oxypentanamide;

N-phenyl-N-methyl-5-(2-nitro-3-formylphenyl)oxypentanamide;

N-cyclohexyl-N-methyl-5-(2-nitro-3-formylphenyl)oxypentanamide;

(±)-decahydroquinolinyl-5-(2-nitro-3-formylphenyl)oxypentanamide;

N-diphenylmethyl-N-methyl-5-(2-nitro-3-formylphenyl)oxypentanamide;

N-cyclohexyl-N-hydroxyethyl-5-(3-nitro-4-formylphenyl)oxypentanamide;

N-cyclohexyl-N-methyl-5-(3-nitro-4-formylphenyl)oxypentanamide;

N-phenyl-N-methyl-5-(3-nitro-4-formylphenyl)oxypentanamide;

(±)-decahydroquinolinyl-5-(3-nitro-4-formylphenyl)oxypentanamide;

N-cyclohexyl-N-3-hydroxypropyl-2-(3-formyl-4-nitrophenyl)oxyacetamide;

N-cyclohexyl-N-hydroxypropyl-2-(3-formyl-4-nitrophenyl)oxyacetamide;

N-phenyl-N-hydroxypropyl-2-(3-formyl-4-nitrophenyl)oxyacetamide;

N-cyclohexyl-N-butyl-2-(3-formyl-4-nitrophenyl)oxyacetamide;

(±)-decahydroquinolinyl-2-(3-formyl-4-nitrophenyl)oxyacetamide;

N-cyclohexyl-N-hydroxyethyl-2-(2-formyl-3-nitro-4-chlolophenyl)oxyacetamide;

N-cyclohexyl-N-hydroxymethyl-2-(2-formyl-3-nitrophenyl)oxyacetamide;

N-cyclohexyl-N-propyl-2-(2-formyl-3-nitrophenyl)oxyacetamide;

N-phenyl-N-methyl-2-(2-formyl-3-nitrophenyl)oxyacetamide;

N-benzyl-N-hydroxyethyl-2-(2-formyl-3-nitrophenyl)oxyacetamide;

N-cyclohexyl-N-hydroxyethyl-2-(2-nitro-3-formylphenyl)oxyacetamide;

N-phenyl-N-hydroxyethyl-2-(2-nitro-3-formylphenyl)oxyacetamide;

N-cyclohexyl-N-methyl-2-(2-nitro-3-formylphenyl)oxyacetamide;

N-benzyl-N-methyl-2-(2-nitro-3-formylphenyl)oxyacetamide;

(±)-decahydroquinolinyl-2-(2-nitro-3-formylphenyl)oxyacetamide;

N-cyclopentyl-N-hydroxypropyl-2-(3-nitro-4-formylphenyl)oxyacetamide;

N-cyclohexyl-N-methyl-2-(3-nitro-4-formylphenyl)oxyacetamide;

N-benzyl-N-methyl-2-(3-nitro-4-formylphenyl)oxyacetamide;

N-cyclohexyl-N-hydroxypropyl-6-(3-formyl-4-nitrophenyl)oxyhexanamide;

N-cyclohexyl-N-hydroxypropyl-6-(3-formyl-4-nitrophenyl)oxyhexanamide;

N-phenyl-N-hydroxypropyl-6-(3-formyl-4-nitrophenyl)oxyhexanamide;

N-cyclohexyl-N-butyl-6-(3-formyl-4-nitrophenyl)oxyhexanamide;

(±)-decahydroquinolinyl-6-(3-formyl-4-nitrophenyl)oxyhexanamide;

N-cyclohexyl-N-hydroxyethyl-6-(2-formyl-3-nitro-4-chlolophenyl)oxyhexanamide;

N-cyclohexyl-N-hydroxypropyl-6-(2-formyl-3-nitrophenyl)oxyhexanamide;

N-cyclohexyl-N-propyl-6-(2-formyl-3-nitrophenyl)oxyhexanamide;

N-phenyl-N-methyl-6-(2-formyl-3-nitrophenyl)oxyhexanamide;

N-benzyl-N-hydroxyethyl-6-(2-formyl-3-nitrophenyl)oxyhexanamide;

N-cyclohexyl-N-hydroxyethyl-6-(2-nitro-3-formylphenyl)oxyhexanamide;

N-phenyl-N-hydroxyethyl-6-(2-nitro-3-formylphenyl)oxyhexanamide;

N-cyclohexyl-N-methyl-6-(2-nitro-3-formylphenyl)oxyhexanamide;

N-benzyl-N-methyl-6-(2-nitro-3-formylphenyl)oxyhexanamide;

(±)-decahydroquinolinyl-6-(2-nitro-3-formylphenyl)oxyhexanamide;

N-cyclopentyl-N-hydroxypropyl-6-(3-nitro-4-formylphenyl)oxyhexanamide;

N-cyclohexyl-N-methyl-6-(3-nitro-4-formylphenyl)oxyhexanamide; and

N-benzyl-N-methyl-6-(3-nitro-4-formylphenyl)oxyhexanamide.

PREPARATION 5

Compounds wherein R₁ is alkyl are prepared by a two step process thefirst of which is as follows.

Into a tetrahydrofuran solution of methyl Grignard reagent (120 mmol),either purchased from commercial sources or freshly generated from thecorresponding halide and elemental magnesium, was added dropwise asolution of nitroaldehyde (35 g) in tetrahydrofuran (200 ml). Theresulting mixture was warmed to reflux for one hour, then cooled andquenched with saturated aqueous ammonium chloride. Evaporation of thetetrahydrofuran followed by extraction with ethyl acetate providedN-cyclohexyl-N-methyl-4-(3-(1-hydroxyethyl)-4-nitrophenyl)oxybutyramide(30 g).

Proceeding in a similar manner, but substituting the the appropriatereagents and an alkylamide whose preparation is described in Preparation4, there are prepared the following exemplary alcohols:

N-cyclohexyl-N-methyl-4-(3-(1-hydroxyeth-1-yl)-4-nitrophenyl)oxybutyramide;

N-cyclohexyl-N-methyl-4-(3-(1-hydroxybut-1-yl)-4-nitrophenyl)oxybutyramide;

N-cyclohexyl-N-hydroxyethyl-4-(3-(1-hydroxyeth-1-yl)-4-nitrophenyl)oxybutyramide;

N-cyclohexyl-N-methyl-4-(2-(1-hydroxyeth-1-yl)-3-nitrophenyl)oxybutyramide;

N-cyclohexyl-N-hydroxyethyl-4-(2-(1-hydroxyeth-1-yl)-3-nitrophenyl)oxybutyramide;

N-cyclohexyl-N-methyl-4-(2-nitro-3-(1-hydroxyeth-1-yl)phenyl)oxybutyramide;

N-cyclohexyl-N-hydroxyethyl-4-(2-nitro-3-(1-hydroxyeth-1-yl)phenyl)oxybutyramide;

N-cyclohexyl-N-hydroxyethyl-4-(3-(1-hydroxypropyl)-4-nitrophenyl)oxybutyramide;

N-cyclohexyl-N-methyl-(3-(1-hydroxyeth-1-yl)-4-nitrophenyl)oxyheptanamide;

N-cyclohexyl-N-hydroxyethyl-(3-(1-hydroxyeth-1-yl)-4-nitrophenyl)oxyheptanamide;

N-phenyl-N-methyl-(3-(1-hydroxyeth-1-yl)4-nitrophenyl)oxyheptanamide;

N-cyclohexyl-N-methyl-3-(3-(1-hydroxypropyl)-4-nitrophenyl)oxypropanamide;

N-cyclohexyl-N-hydroxyethyl-3-(3-(1-hydroxyeth-1-yl)-4-nitrophenyl)oxypropanamide;

N-cyclopentyl-N-methyl-3-(3-(1-hydroxyeth-1-yl)-4-nitrophenyl)oxypropanamide;

N-cyclohexyl-N-methyl-6-(3-(1-hydroxyeth-1-yl)-4-nitrophenyloxyhexanamide;

N-cyclohexyl-N-hydroxyethyl-6-(3-(1-hydroxypropyl)-4-nitrophenyl)oxyhexanamide;

N-cyclohexyl-N-methyl-5-(3-(1-hydroxyeth-1-yl)-4-nitrophenyl)oxypentanamide;and

N-cyclohexyl-N-hydroxyethyl-5-(3-(1-hydroxyeth-1-yl)-4-nitrophenyl)oxypentanamide.

PREPARATION 6

Oxidation of the secondary alcohols from Preparation 5 is carried out bythe following method.

Anhydrous chromium trioxide, 8 g, was added to a stirred solution of 60ml of dry pyridine in 200 ml of dry dichloromethane and stirred under adry nitrogen atmosphere at about 20° C. for 15 minutes. A solution of 27g ofN-cyclohexyl-N-hydroxyethyl-4-(3-(1-hydroxyethyl)-4-nitrophenyl)oxybutyramidein 150 ml of dry dichloromethane was added and the reaction mixturestirred for an additional 30 minutes at room temperature. The solutionwas decanted from the residue and the residue washed with two 100 ml ofdry diethyl ether. The organic solutions are combined, washedsuccessively with two 200 ml portions of water and dried over anhydroussodium sulphate. Evaporation of the solvent under reduced pressure givesa residue which is crystallized from ethyl acetate to giveN-cyclohexyl-N-hydroxyethyl-4-[(3-(ethan-1-on)-4-nitrophenyl)oxy]butyramide.

Proceeding in a similar manner, the secondary alcohols of Preparation 5may be converted to the corresponding ketone using the above reagentsbut substituting the appropriate secondary alcohol forN-cyclehexyl-N-methyl-4-(3-(1-hydroxyethyl)-4-nitrophenyl)oxybutyramide.Examples are:

N-cyclohexyl-N-methyl-4-(3-(butan-1-on)-4-nitrophenyl)oxybutyramide;

N-cyclohexyl-N-hydroxyethyl-4-(3-(ethan-1-on)-4-nitrophenyl)oxybutyramide;

N-cyclohexyl-N-methyl-4-(2-(ethan-1-on)-3-nitrophenyl)oxybutyramide);

N-cyclohexyl-N-hydroxyethyl-4-(2-(ethan-1-on)-3-nitrophenyl)oxybutyramide;

N-cyclohexyl-N-methyl-4-(2-nitro-3-(ethan-1-on)phenyl)oxybutyramide;

N-cyclohexyl-N-hydroxyethyl-4-(2-nitro-3-(ethan-1-on)phenyl)oxybutyramide;

N-cyclohexyl-N-hydroxyethyl-4-(3-(propan-1-on)-4-nitrophenyl)oxybutyramide;

N-cyclohexyl-N-methyl-7-(3-(ethan-1-on)-4-nitrophenyl)oxyheptanamide;

N-cyclohexyl-N-hydroxyethyl-7-(3-(ethan-1-on)-4-nitrophenyl)oxyheptanamide;

N-cyclohexyl-N-hydroxyethyl-7-(3-phenylmethan-2-on)-4-nitrophenyl)oxyheptanamide;

N-phenyl-N-methyl-7-(3-(ethan-1-on)4-nitrophenyl)oxyheptanamide;

N-cyclohexyl-N-methyl-6-(3-(ethan-1-on)-4-nitrophenyl)oxyhexanamide;

N-cyclohexyl-N-hydroxyethyl-6-(3-(propan-1-on)-4-nitrophenyl)oxyhexanamide;

N-cyclohexyl-N-methyl-5-(3-(ethan-1-on)-4-nitrophenyl)oxypentanamide;and

N-cyclohexyl-N-hydroxyethyl-5-(3-(ethan-1-on)-4-nitrophenyl)oxypentanamide.

PREPARATION 7

Preparation of 5-(N-cyclohexyl-N-methyl-4-butyramide)oxy-2-nitrobenzoicacid and analogues as illustrated by Formula (11) in Reaction Scheme B.

To a solution of5-(N-cyclohexyl-N-methyl-4-butyramide)oxy-2-nitrobenzaldehyde (3.5 g) indry pyridine (20 ml) under a blanket of nitrogen was added solidtetra-N-butylammonium permanganate portionwise over 1 hour. The reactionwas stirred at room temperature for 1 hour and was then poured intoethyl acetate/6M hydrogen chloride (100 ml each). Solid sodium bisulfitewas added to decolorize the solution and the layers were separated. Theaqueous layer was washed with ethyl acetate (2×50 ml). The combinedorganic layers were washed with 1M HCl (3×50 ml) and brine (2×50 ml),dried, filtered and evaporated to give a syrup which foamed at highvacuum from dichloromethane to yield5-(N-cyclohexyl-N-methyl-4-butyramide)oxy-2-nitrobenzoic acid as anamorphous solid.

Following this procedure, all of the aldehydes of Preparation 4 areconverted to the corresponding acid.

PREPARATION 8

Reduction of the nitroacid compounds from Preparation 7 to theiranthranilic acid analog is carried out using the following reagents andconditions.

2-nitro-5-(N-cyclohexyl-N-methyl-4-butyramide)oxybenzoic acid (78.7 g)was dissolved in absolute ethanol (750 ml) and hydrogenated at 60 psiover 10% Pd-C (6 g) overnight. The catalyst was removed by filtrationthrough a pad of Celite, and was thoroughly washed with additionalethanol (250 ml). The combined filtrates were thoroughly evaporated togive a thick syrup which crystallized from hexane/dichloromethane toafford 2-amino-5-(N-cyclohexyl-N-methyl-butyramid-4-yl)oxybenzoic acidas a yellow powder, m.p. 175°-176° C.

Proceeding in a similar manner, but substituting the appropriatenitroacid for 2-amino-5-(N-cyclohexyl-N-methyl-butyramid-4-yl)oxybenzoicacid all the nitroacids prepared as per Preparation 7 may be reduced tothe corresponding amine.

PREPARATION 9 Ethyl 4-(7oxy-1,2,3,5-tetrahydroimadazo[2,1-b]quinazolin-7-yl)oxybutyrate

To a solution of7-hydroxy-1,2,3,5-tetrahydroimadazo[2,1-b]quinazolin-2-one (2.6 g) madeas per U.S. Pat. No. 3,932,407 and ethyl 4-bromobutyrate (1.72 ml) in100 ml dimethylformamide was added 1.86 g potassium carbonate. Thereaction mixture was sealed under a blanket of nitrogen and heated to100° C. for 4 hours. The reaction mixture was cooled, poured into 100 mlof water, and the resulting precipitate collected by filtration.Recrystallization from dimethylformamide-water gave 3.24 g of ethyl4-(2-oxo-1,2,3,5-tetrahydroimadazole[2,1-b]quinazolin-7-yl)oxybutyrate,m.p. 243°-244° C.

PREPARATION 104-(2-oxo-1,2,3,5-tetrahydroimadazo[2,1-b]quinazolin-7-yl)oxybutyric acid

To a suspension of ethyl4-(2-oxo-1,2,3,5-tetrahydroimadazo[2,1-b]quinazolin-7-yl)oxybutyrate (65g) in ethanol (1000 ml) was added 3N NaOH (100 ml) in small portions.After 30 minutes at room temperature the reaction mixture was acidifiedwith concentrated HCl. The resulting thick precipitate was collected byfiltration and/or centrifugation and dried to give4-(2-oxo-1,2,3,5-tetrahydroimadazo[2,1-b]quinazolin-7-yl)oxybutyric acid(m.p.>300° C.) quantitatively.

Esters prepared as per Preparation 9 above all may be converted to theircorresponding acid by the foregoing method.

EXAMPLE 1N-(7-(N-cyclohexyl-N-methylbutyramide)oxy-2-aminobenzyl)glycinate

To a solution ofN-cyclohexyl-N-methyl-4-(3-formyl-4-nitrophenyl)oxybutyramide (25 mmol),glycine ethyl ester hydrochloride (6.95 g, 50 mmol) and 3 Å molecularseives (5.0 g) in methanol (75 ml) was added glycine ethyl ester (20.6g, 200 mmol) via syringe. After allowing the solution to stir for 5minutes at room temperature, sodium cyanoborohydride (0.95 g, 15 mmol)was added in one amount. The reaction mixture was allowed to stir atroom temperature for 3-4 hours. The reaction solution was then filteredto remove precipitated solids and molecular seives, and the methanol wasremoved by evaporation. The residue was dissolved in ethyl acetate (300ml) and was washed with 2N sodium hydroxide (2×100 ml) in brine (2×100ml). The organic extract was dried, filtered and evaporated to give athick syrup. Owing to the instability of the oil toward distillation,the compound ethylN-(7-(N-cyclohexyl-N-methylbutyramide)oxy-2-aminobenzyl)glycinate, wasused directly in the next reaction step.

Using this procedure but substituting the appropriate α-amino acid alkylester and alkylamide for the reagents recited above, an α-amino acidester group is added to the aldehyde or ketone functionality of thosecompounds prepared according to Preparations 4 and 6.

EXAMPLE 2 Preparation of N,N-disubstituted4-(2-oxo-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-7-yl)oxybutyramideand related compounds.

A. The thick syrupy residue from Example 1 above was dissolved inabsolute ethanol (100 ml) and hydrogenated over 10% Pd-C (1.0 g) untiluptake of hydrogen ceased, approximately 4 hours. The catalyst wasremoved by filtration through a pad of Celite, and pad was washed cleanwith absolute ethanol (50 ml).

B. The combined filtrates from the previous paragraph were treated withcyanogen bromide (3.20 g, 30 mmol), and the resulting solutionmaintained at a reflux for 16 hours. Upon cooling, the ethanol wasremoved, and the residue was dissolved in ethanol (100 ml) and treatedwith 6N sodium hydroxide (5 ml, 30 mmol) and stirred for 2 hours at roomtemperature. The product precipitated from this mixture as an off-whiteto tan powder. The powder was further purified by filtration and a waterwash and dried, yieldingN-cyclohexyl-N-methyl-4-(2-oxo-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-7-yl)oxybutyramide,m.p. 243°-244° C.

Proceeding in a like manner but substituting the appropriate compoundprepared as per Preparation 7 for ethylN-[(7-(N-cyclohexyl-N-methylbutyramid-4-yl)oxy)-2-aminobenzyl)methyl]glycinate,there may be prepared the following exemplary compounds of Formula I:

N-cyclohexyl-N-(2-hydroxyethyl)-4-(2-oxo-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-7-yl)oxybutyramide,m.p. 185°-186° C.;

N-cyclohexylmethyl-N-(2-hydroxyethyl)-4-(2-oxo-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-7-yl)oxybutyramide;

N-phenyl-N-methyl-4-(2-oxo-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-7-yl)oxybutyramide,m.p. 223°-224° C.;

N-cyclohexylmethyl-N-(2-hydroxyethyl)-4-(2-oxo-5-methyl-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-7-yl)oxybutyramide;

N-phenyl-N-methyl-4-(2-oxo-3-methyl-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-7-yl)oxybutyramide;

N-cyclohexyl-N-(2-hydroxyethyl)-4-(2-oxo-6-chloro-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-7-yl)oxybutyramide;

N-cyclohexyl-N-(2-morpholinylethyl)-4-(2-oxo-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-7-yl)oxybutyramide,m.p. 115°-117° C.;

N-cyclohexyl-N-n-butyl-4-(2-oxo-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-7-yl)oxybutyramide,m.p. 170°-172° C.;

N-cycloheptyl-N-methyl-4-(2-oxo-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-7-yl)oxybutyramide,m.p. 226°-228° C.;

N-cyclohexyl-N-(2-methoxyethyl)-4-(2-oxo-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-7-yl)oxybutyramide,m.p. 186°-187° C.;

N-cyclohexyl-N-(2-hydroxyethyl)-4-(2-oxo-6-methoxy-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-7-yl)oxybutyramide;

N-cyclohexylmethyl-N-(2-hydroxyethyl)-4-(2-oxo-3-methyl-6-chloro-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-7-yl)oxybutyramide;

N-cyclohexylbutyl-N-(2-hydroxyethyl)-4-(2-oxo-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-7-yl)oxybutyramide;

N-cyclohexyl-N-(2-hydroxyethyl)-4-(2-oxo-6-methyl-1,2,3,5-tetrahydroimidazo[2,1-b]qinazolin-7-yl)oxybutyramide;

N-cyclohexyl-N-(6-hydroxyhexyl)-4-(2-oxo-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-7-yl)oxybutyramide;

N-cyclohexyl-N-methyl-4-(2-oxo-6-chloro-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-7-yl)oxybutyramide;

N-benzyl-N-methyl-4-(2-oxo-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-7-yl)oxybutyramide,m.p. 232°-234° C.;

N,N-dibenzyl-4-(2-oxo-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-7-yl)oxybutyramide,m.p. 194°-196° C.;

N,N-dicyclohexyl-4-(2-oxo-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-7-yl)oxybutyramide,m.p. 242°-244° C.;

morpholinyl-4-(2-oxo-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-7-yl)oxybutyramide,m.p. 288°-290° C.;

N-cyclohexylbutyl-N-(2-hydroxyethyl)-4-(2-oxo-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-7-yl)oxybutyramide;

piperidinyl-4-(2-oxo-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-7-yl)oxybutyramide,m.p. 276°-278° C.;

pyrrolidinyl-4-(2-oxo-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-7-yl)oxybutyramide,m.p. 278°-280° C.;

perhexylenyl-4-(2-oxo-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-7-yl)oxybutyramide,m.p. 217°-218° C.;

N-cyclooctyl-N-methyl-4-(2-oxo-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-7-yl)oxybutyramide,m.p. 234°-235° C.;

N-cyclopentyl-N-methyl-4-(2-oxo-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-7-yl)oxybutyramide,m.p. 262°-263° C.;

N-cyclopentyl-N-(2-hydroxyethyl)-4-(2-oxo-6-chloro-1,-2,3,5-tetrahydroimidazo[2,1-b]quinazolin-7-yl)oxybutyramide;

N-cyclopentylmethyl-N-(2-hydroxyethyl)-4-(2-oxo-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-7-yl)oxybutyramide;

N-cyclohexyl-N-ethyl-4-(2-oxo-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-7-yl)oxybutyramide,m.p. 220°-221° C.;

N-cyclohexyl-N-isopropyl-4-(2-oxo-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-7-yl)oxybutyramide,m.p. 244°-246° C.;

N-methylpiperazinyl-4-(2-oxo-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-7-yl)oxybutyramide;

tetrahydroquinolinyl-4-(2-oxo-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-7-yl)oxybutyramide,m.p. 203°-204° C.;

tetrahydroisoquinolinyl-4-(2-oxo-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-7-yl)oxybutyramide,m.p. 216°-218° C.;

indolinyl-4-(2-oxo-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-7-yl)oxybutyramide,m.p. 264°-266° C.;

(±)-decahydroquinloninyl-4-(2-oxo-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-7-yl)oxybutyramide,m.p. 218°-220° C.;

N-diphenylmethyl-N-methyl-4-(2-oxo-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-7-yl)oxybutyramide,m.p. 232°-234° C.;

N,N-dimethyl-4-(2-oxo-9-methyl-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-7-yl)oxybutyramide;

N-methyl-N-hexyl-4-(2-oxo-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-7-yl)oxybutyramide;

N,N-di-n-hexyl-4-(2-oxo-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-7-yl)oxybutyramide;

N-methyl-N-hydroxypropyl-4-(2-oxo-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-7-yl)oxybutyramide;

N-n-hexyl-N-(2-hydroxyethyl)-4-(2-oxo-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-7-yl)oxybutyramide;

N,N-di(2-hydroxyethyl)-4-(2-oxo-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-7-yl)oxybutyramide;

N-phenyl-N-(2-hydroxyethyl)-4-(2-oxo-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-7-yl)oxybutyramide;

N-phenyl-N-n-hexyl-4-(2-oxo-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-7-yl)oxybutyramide;

N-benzyl-N-ethyl-4-(2-oxo-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-7-yl)oxybutyramide;

N-benzyl-N-(2-hydroxyethyl)-4-(2-oxo-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-7-yl)oxybutyramide;

N-(4-chlorobenzyl)-N-methyl-4-(2-oxo-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-7-yl)oxybutyramide;

N-(4-methoxybenzyl)-N-methyl-4-(2-oxo-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-7-yl)oxybutyramide;

N-cyclohexyl-N-methyl-4-(2-oxo-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-6-yl)oxybutyramide,m.p. 256°-258° C.;

N-cyclohexylbutyl-N-(2-hydroxyethyl)-4-(2-oxo-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-6-yl)oxybutyramide;

N-cyclohexylmethyl-N-(2-hydroxyethyl)-4-(2-oxo-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-6-yl)oxybutyramide;

N-phenyl-N-methyl-4-(2-oxo-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-6-yl)oxybutyramide;

N-cyclohexyl-N-(2-hydroxyethyl)-4-(2-oxo-7-chloro-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-6-yl)oxybutyramide;

N-cyclohexyl-N-(2-hydroxyethyl)-N-(2-oxo-7-methyl-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-6-yl)oxybutyramide;

N-cyclohexyl-N-methyl-4-(2-oxo-9-chloro-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-6-yl)oxybutyramide;

N-benzyl-N-methyl-4-(2-oxo-1,2,3,5-tetrahydroimidazo[2,1-b]-6-oxoquinazolin-6-yl)oxybutyramide;

N-cyclopentyl-N-(2-hydroxyethyl)-4-(2-oxo-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-6-yl)oxybutyramide;

N-cyclopentylmethyl-N-(2-hydroxyethyl)-4-(2-oxo-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-6-yl)oxybutyramide;

(±)-decahydroquinolinyl-4-(2-oxo-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-6-yl)oxybutyramide;

N-diphenylmethyl-N-methyl-4-(2-oxo-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-6-yl)oxybutyramide;

N-methyl-N-hydroxypropyl-4-(2-oxo-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-6-yl)oxybutyramide;

N-cyclohexyl-N-(6-hydroxyhexyl)-4-(2-oxo-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-6-yl)oxybutyramide;

N-phenyl-N-(2-hydroxyethyl)-4-(2-oxo-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-6-yl)oxybutyramide;

N-phenyl-N-hexyl-4-(2-oxo-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-6-yl)oxybutyramide;

N-(4-chlorobenzyl)-N-(2-hydroxyethyl)-4-(2-oxo-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-6-yl)oxybutyramide;

N-(4-methoxybenzyl)-N-methyl-4-(2-oxo-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-6-yl)oxybutyramide;

N-cyclohexyl-N-(2-hydroxyethyl)-4-(2-oxo-6-methyl-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-8-yl)oxybutyramide;

N-cyclohexyl-N-(2-hydroxyethyl)-4-(2-oxo-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-8-yl)oxybutyramide;

N-cyclohexyl-N-(2-hydroxyethyl)-4-(2-oxo-6-methyl-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-8-yl)oxybutyramide;

N-cyclohexylmethyl-N-(2-hydroxyethyl)-4-(2-oxo-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-8-yl)oxybutyramide;

N-cyclohexyl-N-(2-hydroxyethyl)-4-(2-oxo-6-chloro-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-8-yl)oxybutyramide;

N-cyclohexylbutyl-N-(2-hydroxyethyl)-4-(2-oxo-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-8-yl)oxybutyramide;

N-cyclohexyl-N-methyl-4-(2-oxo-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-8-yl)oxybutyramide,m.p. 113°-114° C.;

N-phenyl-N-methyl-4-(2-oxo-1,2,3,5-tetrahydroimidazo[2,1-b]-7-oxoquinazolin-7-yl)oxybutyramide;

N-cyclohexyl-N-(2-hydroxyethyl)-4-(2-oxo-7-chloro-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-8-yl)oxybutyramide;

N-cyclohexyl-N-(2-hydroxyethyl)-4-(2-oxo-7-methyl-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-8-yl)oxybutyramide;

N-cyclohexyl-N-methyl-4-(2-oxo-9-chloro-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-8-yl)oxybutyramide;

N-benzyl-N-methyl-4-(2-oxo-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-8-yl)oxybutyramide;

N-cyclopentyl-N-(2-hydroxyethyl)-4-(2-oxo-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-8-yl)oxybutyramide;

N-cyclopentylbutyl-N-(2-hydroxyethyl)-4-(2-oxo-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-8-yl)oxybutyramide;

(±)-decahydroquinolinyl-4-(2-oxo-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-8-yl)oxybutyramide;

N-diphenylmethyl-N-methyl-4-(2-oxo-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-8-yl)oxybutyramide;

N-cyclohexyl-N-(6-hydroxyhexyl)-4-(2-oxo-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-8-yl)oxybutyramide;

N-phenyl-N-(2-hydroxyethyl)-4-(2-oxo-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-8-yl)oxybutyramide;

N-phenyl-N-hexyl-4-(2-oxo-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-8-yl)oxybutyramide;

N-(4-chlorobenzyl)-N-(2-hydroxyethyl)-4-(2-oxo-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-8-yl)oxybutyramide;

N-(4-methoxybenzyl)-N-ethyl-4-(2-oxo-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-8-yl)oxybutyramide;

N-cyclohexyl-N-(6-hydroxyhexyl)-4-(2-oxo-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-8-yl)oxybutyramide;

N-cyclohexyl-N-(2-hydroxyethyl)-4-(2-oxo-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-9-yl)oxybutyramide;

N-cyclopentyl-N-(2-hydroxyethyl)-4-(2-oxo-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-9-yl)oxybutyramide;

N-phenyl-N-methyl-4-(2-oxo-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-9-yl)oxybutyramide;

N-cyclohexyl-N-(2-hydroxyethyl)-4-(2-oxo-6-chloro-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-9-yl)oxybutyramide;

N-cyclohexylbutyl-N-(2-hydroxyethyl)-4-(2-oxo-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-9-yl)oxybutyramide;

N-cyclohexyl-N-methyl-4-(2-oxo-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-9-yl)oxybutyramide,m.p. 110°-111° C.;

N-benzyl-N-methyl-4-(2-oxy-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-9-yl)oxybutyramide;

N-cyclopentyl-N-(2-hydroxyethyl)-4-(2-oxy-6-methyl-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-9-yl)oxybutyramide;

N-diphenylmethyl-N-methyl-4-(2-oxo-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-9-yl)oxybutyramide;

N-cyclohexyl-N-(6-hydroxyhexyl)-4-(2-oxo-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-9-yl)oxybutyramide;

N-phenyl-N-(2-hydroxyethyl)-4-(2-oxo-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-9-yl)oxybutyramide;

N-cyclohexyl-N-(2-hydroxyethyl)-7-(2-oxo-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-7-yl)oxyheptanamide;

N-cyclohexylmethyl-N-(2-hydroxyethyl)-7-(2-oxo-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-7-yl)oxyheptanamide;

N-phenyl-N-methyl-7-(2-oxo-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-7-yl)oxyheptanamide;

N-cyclohexylmethyl-N-(2-hydroxyethyl)-7-(2-oxo-5-methyl-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-7-yl)oxyheptanamide;

N-phenyl-N-(2-hydroxyethyl)-7-(2-oxo-3-methyl-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-7-yl)oxyheptanamide;

N-cyclohexyl-N-(2-hydroxyethyl)-7-(2-oxo-6-chloro-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-7-yl)oxyheptanamide;

N-cyclohexyl-N-(2-hydroxyethyl)-7-(2-oxo-3-methyl-6-chloro-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-7-yl)oxyheptanamide;

N-cyclopentylbutyl-N-(2-hydroxyethyl)-7-(2-oxo-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-7-yl)oxyheptanamide;

N-cyclohexyl-N-(2-hydroxyethyl)-7-(2-oxo-6-methyl-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-7-yl)oxyheptanamide;

N-cyclohexyl-N-methyl-7-(2-oxo-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-7-yl)oxyheptanamide,m.p. 148°-150° C.;

N-cyclohexyl-N-(6-hydroxyhexyl)-7-(2-oxo-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-7-yl)oxyheptanamide;

N-cyclohexyl-N-methyl-7-(2-oxo-6-chloro-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-7-yl)oxyheptanamide;

N-cyclohexyl-N-(2-hydroxyethyl)-7-(2-oxo-6-methoxy-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-7-yl)oxyheptanamide;

N-benzyl-N-methyl-7-(2-oxo-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-7-yl)oxyheptanamide;

N-cyclohexylbutyl-N-(2-hydroxyethyl)-7-(2-oxo-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-7-yl)oxyheptanamide;

N-cyclohexyl-N-(2-hydroxyethyl)-7-(2-oxo-6-methoxy-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-7-yl)oxyheptanamide;

N-cyclopentyl-N-(2-hydroxyethyl)-7-(2-oxo-6-chloro-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-7-yl)oxyheptanamide;

(±)-decahydroquinolinyl-7-(2-oxo-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-7-yl)oxyheptanamide;

N-diphenylmethyl-N-methyl-7-(2-oxo-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-7-yl)oxyheptanamide;

N-methyl-N-n-hexyl-7-(2-oxo-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-7-yl)oxyheptanamide;

N-n-hexyl-N-(2-hydroxyethyl)-7-(2-oxo-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-7-yl)oxyheptanamide;

N-phenyl-N-(2-hydroxyethyl)-7-(2-oxo-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-7-yl)oxyheptanamide;

N-phenyl-N-n-hexyl-7-(2-oxo-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-7-yl)oxyheptanamide;

N-benzyl-N-(2-hydroxyethyl)-7-(2-oxo-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-7-yl)oxyheptanamide;

N-(4-chlorobenzyl)-N-methyl-7-(2-oxo-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-7-yl)oxyheptanamide;

N-(4-methoxybenzyl)-N-methyl-7-(2-oxo-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-7-yl)oxyheptanamide;

N-cyclohexylbutyl-N-(2-hydroxyethyl)-7-(2-oxo-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-6-yl)oxyheptanamide;

N-phenyl-N-methyl-7-(2-oxo-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-6-yl)oxyheptanamide;

N-cyclohexyl-N-(2-hydroxyethyl)-7-(2-oxo-7-chloro-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-6-yl)oxyheptanamide;

N-cyclohexyl-N-(2-hydroxyethyl)-7-(2-oxo-7-methyl-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-6-yl)oxyheptanamide;

N-cyclohexyl-N-methyl-7-(2-oxo-9-chloro-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-6-yl)oxyheptanamide;

N-benzyl-N-methyl-7-(2-oxo-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-6-yl)oxyheptanamide;

N-cyclopentyl-N-(2-hydroxyethyl)-7-(2-oxo-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-6-yl)oxyheptanamide;

N-cyclopentylbutyl-N-(2-hydroxyethyl)-7-(2-oxo-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-6-yl)oxyheptanamide;

(±)-decahydroquinolinyl-7-(2-oxo-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-6-yl)oxyheptanamide;

N-cyclohexyl-N-(6-hydroxyhexyl)-7-(2-oxo-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-6-yl)oxyheptanamide;

N-phenyl-N-(2-hydroxyethyl)-7-(2-oxo-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-6-yl)oxyheptanamide;

N-phenyl-N-hexyl-7-(2-oxo-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-6-yl)oxyheptanamide;

N-(4-chlorobenzyl)-N-(2-hydroxyethyl)-7-(2-oxo-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-6-yl)oxyheptanamide;

N-(4-methoxybenzyl)-N-methyl-7-(2-oxo-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-6-yl)oxyheptanamide;

N-cyclohexyl-N-(2-hydroxyethyl)-7-(2-oxo-6-methyl-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-8-yl)oxyheptanamide;

N-cyclohexyl-N-(2-hydroxyethyl)-7-(2-oxo-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-8-yl)oxyheptanamide;

N-cyclohexylbutyl-N-(2-hydroxyethyl)-7-(2-oxo-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-8-yl)oxyheptanamide;

N-cyclohexyl-N-(2-hydroxyethyl)-7-(2-oxo-6-chloro-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-8-yl)oxyheptanamide;

N-phenyl-N-methyl-7-(2-oxo-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-8-yl)oxyheptanamide;

N-cyclohexyl-N-(2-hydroxyethyl)-7-(2-oxo-7-chloro-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-8-yl)oxyheptanamide;

N-cyclohexyl-N-(2-hydroxyethyl)-7-(2-oxo-7-methyl-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-8-yl)oxyheptanamide;

N-benzyl-N-methyl-7-(2-oxo-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-8-yl)oxyheptanamide;

N-cyclopentyl-N-(2-hydroxyethyl)-7-(2-oxo-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-8-yl)oxyheptanamide;

N-cyclopentylmethyl-N-methyl-7-(2-oxo-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-8-yl)oxyheptanamide;

N-cyclopentylbutyl-N-(2-hydroxyethyl)-7-(2-oxo-1,2,-3,5-tetrahydroimidazo[2,1-b]quinazolin-8-yl)oxyheptanamide;

(±)-decahydroquinolinyl-7-(2-oxo-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-8-yl)oxyheptanamide;

N-diphenylmethyl-N-methyl-7-(2-oxo-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-8-yl)oxyheptanamide;

N-phenyl-N-(2-hydroxyethyl)-7-(2-oxo-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-8-yl)oxyheptanamide;

N-phenyl-N-hexyl-7-(2-oxo-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-8-yl)oxyheptanamide;

N-(4-chlorobenzyl)-N-(2-hydroxyethyl)-7-(2-oxo-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-8-yl)oxyheptanamide;

N-cyclohexyl-N-(6-hydroxyhexyl)-7-(2-oxo-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-8-yl)oxyheptanamide;

N-cyclohexyl-N-(2-hydroxyethyl)-7-(2-oxo-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-9-yl)oxyheptanamide;

N-cyclopentyl-N-(2-hydroxyethyl)-7-(2-oxo-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-9-yl)oxyheptanamide;

N-phenyl-N-methyl-7-(2-oxo-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-9-yl)oxyheptanamide;

N-cyclohexylbutyl-N-(2-hydroxyethyl)-7-(2-oxo-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-9-yl)oxyheptanamide;

N-cyclohexyl-N-methyl-7-(2-oxo-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-9-yl)oxyheptanamide;

N-benzyl-N-methyl-7-(2-oxy-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-9-yl)oxyheptanamide;

N-cyclopentyl-N-(2-hydroxyethyl)-7-(2-oxy-6-methyl-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-9-yl)oxyheptanamide;

N-cyclohexyl-N-(6-hydroxyhexyl)-7-(2-oxo-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-9-yl)oxyheptanamide;

N-phenyl-N-(2-hydroxyethyl)-7-(2-oxo-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-9-yl)oxyheptanamide;

(±)-decahydroquinolinyl-N-methyl-7-(2-oxo-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-9-yl)oxyheptanamide;N-cyclohexyl-N-(2-hydroxyethyl)-2-(2-oxo-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-7-yl)oxyacetamide;

N-phenyl-N-methyl-2-(2-oxo-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-7-yl)oxyacetamide;

N-cyclohexylmethyl-N-(2-hydroxyethyl)-2-(2-oxo-5-methyl-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-7-yl)oxyacetamide;

N-phenyl-N-(2-hydroxyethyl)-2-(2-oxo-3-methyl-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-7-yl)oxyacetamide;

N-cyclohexyl-N-(2-hydroxyethyl)-2-(2-oxo-6-chloro-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-7-yl)oxyacetamide;

N-cyclohexyl-N-methyl-2-(2-oxo-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-7-yl)oxyacetamide,m.p. 237°-239° C.;

N-cyclohexyl-N-(2-hydroxyethyl)-2-(2-oxo-3-methyl-6-chloro-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-7-yl)oxyacetamide;

N-cyclopentylbutyl-N-(2-hydroxyethyl)-2-(2-oxo-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-7-yl)oxyacetamide;

N-cyclohexyl-N-(2-hydroxyethyl)-2-(2-oxo-6-methyl-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-7-yl)oxyacetamide;

N-cyclopentyl-N-(2-hydroxyethyl)-2-(2-oxo-6-chloro-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-7-yl)oxyacetamide;

(±)-decahydroquinolinyl-2-(2-oxo-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-7-yl)oxyacetamide;

N-n-hexyl-N-(2-hydroxyethyl)-2-(2-oxo-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-7-yl)oxyacetamide;

N-cyclohexylbutyl-N-(2-hydroxyethyl)-2-(2-oxo-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-6-yl)oxyacetamide;

N-phenyl-N-methyl-2-(2-oxo-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-6-yl)oxyacetamide;

N-cyclohexyl-N-(2-hydroxyethyl)-2-(2-oxo-7-chloro-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-6-yl)oxyacetamide;

N-benzyl-N-methyl-2-(2-oxo-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-6-yl)oxyacetamide;

N-cyclopentyl-N-(2-hydroxyethyl)-2-(2-oxo-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-6-yl)oxyacetamide;

N-cyclohexyl-N-(2-hydroxyethyl)-2-(2-oxo-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-8-yl)oxyacetamide;

N-cyclohexylbutyl-N-(2-hydroxyethyl)-2-(2-oxo-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-8-yl)oxyacetamide;

N-phenyl-N-methyl-2-(2-oxo-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-8-yl)oxyacetamide;

N-cyclopentyl-N-(2-hydroxyethyl)-2-(2-oxo-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-8-yl)oxyacetamide;

N-cyclopentylmethyl-N-methyl-2-(2-oxo-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-8-yl)oxyacetamide;

(±)-decahydroquinolinyl-2-(2-oxo-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-8-yl)oxyacetamide;

N-cyclohexyl-N-(2-hydroxyethyl)-2-(2-oxo-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-9-yl)oxyacetamide;

N-cyclopentyl-N-(2-hydroxyethyl)-2-(2-oxo-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-9-yl)oxyacetamide;

N-phenyl-N-methyl-2-(2-oxo-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-9-yl)oxyacetamide;

N-cyclohexyl-N-methyl-2-(2-oxo-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-9-yl)oxyacetamide;

N-benzyl-N-methyl-2-(2-oxo-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-9-yl)oxyacetamide;

N-cyclohexyl-N-(6-hydroxyhexyl)-2-(2-oxo-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-9-yl)oxyacetamide;

N-cyclohexyl-N-(2-hydroxyethyl)-5-(2-oxo-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-7-yl)oxypentanamide;

N-cyclohexylmethyl-N-(2-hydroxyethyl)-5-(2-oxo-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-7-yl)oxypentanamide;

N-phenyl-N-methyl-5-(2-oxo-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-7-yl)oxypentanamide;

N-cyclohexylmethyl-N-(2-hydroxyethyl)-5-(2-oxo-5-methyl-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-7-yl)oxypentanamide;

N-phenyl-N-(2-hydroxyethyl)-5-(2-oxo-3-methyl-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-7-yl)oxypentanamide;

N-cyclohexyl-N-(2-hydroxyethyl)-5-(2-oxo-6-chloro-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-7-yl)oxypentanamide;

N-cyclohexyl-N-(2-hydroxyethyl)-5-(2-oxo-3-methyl-6-chloro-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-7-yl)oxypentanamide;

N-cyclohexyl-N-methyl-5-(2-oxo-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-7-yl)oxypentanamide,m.p. 206°-208° C.;

N-cyclopentylbutyl-N-(2-hydroxyethyl)-5-(2-oxo-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-7-yl)oxypentanamide;

N-cyclohexyl-N-(2-hydroxyethyl)-5-(2-oxo-6-methyl-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-7-yl)oxypentanamide;

N-cyclohexyl-N-(6-hydroxyhexyl)-5-(2-oxo-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-7-yl)oxypentanamide;

N-cyclohexyl-N-methyl-5-(2-oxo-6-chloro-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-7-yl)oxypentanamide;

N-cyclohexyl-N-(2-hydroxyethyl)-5-(2-oxo-6-methoxy-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-7-yl)oxypentanamide;

N-benzyl-N-methyl-5-(2-oxo-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-7-yl)oxypentanamide;

N-cyclohexylbutyl-N-(2-hydroxyethyl)-5-(2-oxo-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-7-yl)oxypentanamide;

N-cyclohexyl-N-(2-hydroxyethyl-5-(2-oxo-6-methoxy-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-7-yl)oxypentanamide;N-cyclopentyl-N-(2-hydroxyethyl)-5-(2-oxo-6-chloro-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-7-yl)oxypentanamide;

(±)-decahydroquinolinyl-5-(2-oxo-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-7-yl)oxypentanamide;

N-diphenylmethyl-N-methyl-5-(2-oxo-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-7-yl)oxypentanamide;

N-methyl-N-n-hexyl-5-(2-oxo-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-7-yl)oxypentanamide;

N-n-hexyl-N-(2-hydroxyethyl)-5-(2-oxo-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-7-yl)oxypentanamide;

N-phenyl-N-(2-hyroxyethyl)-5-(2-oxo-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-7-yl)oxypentanamide;

N-phenyl-N-n-hexyl-5-(2-oxo-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-7-yl)oxypentanamide;

N-benzyl-N-(2-hyroxyethyl)-5-(2-oxo-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-7-yl)oxypentanamide;

N-(4-chlorobenzyl)-N-methyl-5-(2-oxo-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-7-yl)oxypentanamide;

N-(4-methoxybenzyl)-N-methyl-5-(2-oxo-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-7-yl)oxypentanamide;

N-cyclohexylbutyl-N-(2-hydroxyethyl)-5-(2-oxo-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-6-yl)oxypentanamide;

N-phenyl-N-methyl-5-(2-oxo-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-6-yl)oxypentanamide;

N-cyclohexyl-N-(2-hydroxyethyl)-5-(2-oxo-7-chloro-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-6-yl)oxypentanamide;

N-cyclohexyl-N-(2-hydroxyethyl)-5-(2-oxo-7-methyl-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-6-yl)oxypentanamide;

N-cyclohexyl-N-methyl-5-(2-oxo-9-chloro-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-6-yl)oxypentanamide;

N-benzyl-N-methyl-5-(2-oxo-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-6-yl)oxypentanamide;

N-cyclopentyl-N-(2-hydroxyethyl)-5-(2-oxo-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-6-yl)oxypentanamide;

N-cyclopentylbutyl-N-(2-hydroxyethyl)-5-(2-oxo-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-6yl)oxypentanamide;

(±)-decahydroquinolinyl-5-(2-oxo-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-6-yl)oxypentanamide;

N-cyclohexyl-N-(6-hydroxyhexyl)-5-(2-oxo-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-6-yl)oxypentanamide;

N-phenyl-N-(2-hydroxyethyl)-5-(2-oxo-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-6-yl)oxypentanamide;

N-phenyl-N-hexyl-5-(2-oxo-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-6-yl)oxypentanamide;

N-(4-chlorobenzyl)-N-(2-hydroxyethyl)-5-(2-oxo-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-6-yl)oxypentanamide;

N-(4-methoxybenzyl)-N-methyl-5-(2-oxo-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-6-yl)oxypentanamide;

N-cyclohexyl-N-(2-hydroxyethyl)-5-(2-oxo-6-methyl-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-8-yl)oxypentanamide;

N-cyclohexyl-N-(2-hydroxyethyl)-5-(2-oxo-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-8-yl)oxypentanamide;

N-cyclohexyl-N-(2-hydroxyethyl)-5-(2-oxo-6-methoxy-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-8-yl)oxypentanamide;

N-cyclohexylbutyl-N-(2-hydroxyethyl)-5-(2-oxo-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-8-yl)oxypentanamide;

N-cyclohexyl-N-(2-hydroxyethyl)-5-(2-oxo-6-chloro-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-8-yl)oxypentanamide;

N-phenyl-N-methyl-5-(2-oxo-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-8-yl)oxypentanamide;

N-cyclohexyl-N-(2-hydroxyethyl)-5-(2-oxo-7-chloro-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-8-yl)oxypentanamide;

N-cyclohexyl-N-(2-hydroxyethyl)-5-(2-oxo-7-methyl-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-8-yl)oxypentanamide;

N-benzyl-N-methyl-5-(2-oxo-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-8-yl)oxypentanamide;

N-cyclopentyl-N-(2-hydroxyethyl)-5-(2-oxo-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-8-yl)oxypentanamide;

N-cyclopentylmethyl-N-methyl-5-(2-oxo-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-8-yl)oxypentanamide;

N-cyclopentylbutyl-N-(2-hydroxyethyl)-5-(2-oxo-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-8-yl)oxypentanamide;

(±)-decahydroquinolinyl-5-(2-oxo-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-8-yl)oxypentanamide;

N-diphenylmethyl-N-methyl-5-(2-oxo-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-8-yl)oxypentanamide;

N-phenyl-N-(2-hydroxyethyl)-5-(2-oxo-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-8-yl)oxypentanamide;

N-phenyl-n-hexyl-5-(2-oxo-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-8-yl)oxypentanamide;

N-(4-chlorobenzyl)-N-(2-hydroxyethyl)-5-(2-oxo-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-8-yl)oxypentanamide;

N-cyclohexyl-N-(6-hydroxyhexyl)-5-(2-oxo-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-8-yl)oxypentanamide;

N-cyclohexyl-N-(2-hydroxyethyl)-5-(2-oxo-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-9-yl)oxypentanamide;

N-cyclopentyl-N-(2-hydroxyethyl)-5-(2-oxo-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-9-yl)oxypentanamide;

N-phenyl-N-methyl-5-(2-oxo-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-9-yl)oxypentanamide;

N-cyclohexylbutyl-N-(2-hydroxyethyl)-5-(2-oxo-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-9-yl)oxypentanamide;

N-cyclohexyl-N-methyl-5-(2-oxo-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-9-yl)oxypentanamide;

N-benzyl-N-methyl-5-(2-oxy-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-9-yl)oxypentanamide;

N-cyclopentyl-N-(2-hydroxyethyl)-5-(2-oxy-6-methyl-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-9-yl)oxypentanamide;

N-cyclohexyl-N-(6-hydroxyhexyl)-5-(2-oxo-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-9-yl)oxypentanamide;

N-phenyl-N-(2-hydroxyethyl)-5-(2-oxo-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-9-yl)oxypentanamide;

(±)-decahydroquinolinyl-N-methyl-5-(2-oxo-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-9-yl)oxypentanamide;

N-cyclohexyl-N-(2-hyroxyethyl)-6-(2-oxo-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-7-yl)oxyhexanamide;

N-cyclohexylmethyl-N-(2-hydroxyethyl)-6-(2-oxo-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-7-yl)oxyhexanamide;

N-phenyl-N-methyl-6-(2-oxo-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-7-yl)oxyhexanamide;

N-cyclohexylmethyl-N-(2-hydroxyethyl)-6-(2-oxo-5-methyl-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-7-yl)oxyhexanamide;

N-phenyl-N-(2-hydroxyethyl)-6-(2-oxo-3-methyl-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-7-yl)oxyhexanamide;

N-cyclohexyl-N-(2-hydroxyethyl)-6-(2-oxo-6-chloro-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-7-yl)oxyhexanamide;

N-cyclohexyl-N-(2-hydroxyethyl)-6-(2-oxo-3-methyl-6-chloro-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-7-yl)oxyhexanamide;

N-cyclohexylbutyl-N-(2-hydroxyethyl)-6-(2-oxo-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-7-yl)oxyhexanamide;

N-cyclohexyl-N-(2-hydroxyethyl)-6-(2-oxo-6-methyl-1,2,3,4-tetrahydroimidazo[2,1-b]quinazolin-7-yl)oxyhexanamide;N-cyclohexyl-N-(6-hydroxyhexyl)-6-(2-oxo-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-7-yl)oxyhexanamide;

N-cyclohexyl-N-methyl-6-(2-oxo-6-chloro-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-7-yl)oxyhexanamide;

N-cyclohexyl-N-(2-hydroxyethyl)-6-(2-oxo-6-methoxy-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-7-yl)oxyhexanamide;

N-benzyl-N-methyl-6-(2-oxo-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-7-yl)oxyhexanamide;

N-cyclohexylbutyl-N-(2-hydroxyethyl)-6-(2-oxo-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-7-yl)oxyhexanamide;

N-cyclohexyl-N-(2-hydroxyethyl)-6-(2-oxo-6-methoxy-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-7-yl)oxyhexanamide;

N-cyclohexyl-N-methyl-6-(2-oxo-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-7-yl)oxyhexanamide,m.p. 208°-209° C.;

N-cyclohexyl-N-(2-hydroxyethyl)-6-(2-oxo-6-chloro-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-7-yl)oxyhexanamide;

(±)-decahydroquinolinyl-6-(2-oxo-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-7-yl)oxyhexanamide;

N-diphenylmethyl-N-methyl-6-(2-oxo-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-7-yl)oxyhexanamide;

N-methyl-N-n-hexyl-6-(2-oxo-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-7yl)oxyhexanamide;

N-n-hexyl-N-(2-hydroxyethyl)-6-(2-oxo-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-7-yl)oxyhexanamide;

N-phenyl-N-(2-hydroxyethyl)-6-(2-oxo-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-7-yl)oxyhexanamide;

N-phenyl-N-n-hexyl-6-(2-oxo-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-7-yl)oxyhexanamide;

N-benzyl-N-(2-hydroxyethyl)-6-(2-oxo-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-7-yl)oxyhexanamide;

N-(4-chlorobenzyl)-N-methyl-6-(2-oxo-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-7-yl)oxyhexanamide;

N-(4-methoxybenzyl)-N-methyl-6-(2-oxo-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-7-yl)oxyhexanamide;

N-cyclohexylbutyl-N-(2-hydroxyethyl)-6-(2-oxo-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-6-yl)oxyhexanamide;

N-phenyl-N-methyl-6-(2-oxo-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-6-yl)oxyhexanamide;

N-cyclohexyl-N-(2-hydroxyethyl)-4-(2-oxo-7-chloro-1,2,3,5-tetrahydroimidazo[2,1b]quinazolin-6-yl)oxyhexanamide;

N-cyclohexyl-N-(2-hydroxyethyl)-4-(2-oxo-7-methyl-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-6-yl)oxyhexanamide;

N-cyclohexyl-N-methyl-6-(2-oxo-9-chloro-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-6-yl)oxyhexanamide;

N-benzyl-N-methyl-6-(2-oxo-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-6-yl)oxyhexanamide;

N-cyclopentyl-N-(2-hydroxyethyl)-6-(2-oxo-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-6-yl)oxyhexanamide;

N-cyclopentylbutyl-N-(2-hydroxyethyl)-6-(2-oxo-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-6-yl)oxyhexanamide;

(±)-decahydroquinolinyl-6-(2-oxo-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-6-yl)oxyhexanamide;

N-cyclohexyl-N-(6-hydroxyhexyl)-6-(2-oxo-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-6-yl)oxyhexanamide;

N-phenyl-N-(2-hydroxyethyl)-6-(2-oxo-1,2,3,5-tetrahydoimidazo[2,1-b]quinazolin-6-yl)oxyhexanamide;

N-phenyl-N-hexyl-6-oxo-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-6-yl)oxyhexanamide;

N-(4-chlorobenzyl)-N-(2-hydroxyethyl)-6-(2-oxo-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-6-yl)oxyhexanamide;

N-(4-methoxybenzyl)-N-methyl-6-(2-oxo-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-6-yl)oxyhexanamide;

N-cyclohexyl-N-(2-hydroxyethyl)-6-(2-oxo-6-methyl-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-8-yl)oxyhexanamide;

N-cyclohexyl-N-(2-hydroxyethyl)-6-(2-oxo-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-8-yl)oxyhexanamide;

N-cyclohexyl-N-(2-hydroxyethyl)-6-(2-oxo-6-methoxy-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-8-yl)oxyhexanamide;

N-cyclohexylbutyl-N-(2-hydroxyethyl)-6-(2-oxo-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-8-yl)oxyhexanamide;

N-cyclohexyl-N-(2-hydroxyethyl)-6-(2-oxo-6-chloro-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-8-yl)oxyhexanamide;

N-phenyl-N-methyl-6-(2-oxo-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-8-yl)oxyhexanamide;

N-cyclohexyl-N-(2-hydroxyethyl)-6-(2-oxo-7-chloro-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-8-yl)oxyhexanamide;

N-cyclohexyl-N-(2-hydroxyethyl)-6-(2-oxo-7-methyl-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-8-yl)oxyhexanamide;

N-benzyl-N-methyl-6-(2-oxo-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-8-yl)oxyhexanamide;

N-cyclopentyl-N-(2-hydroxyethyl)-6-(2-oxo-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-8-yl)oxyhexanamide;

N-cyclopentylmethyl-N-methyl-6-(2-oxo-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-8-yl)oxyhexanamide;

N-cyclopentylbutyl-N-(2-hydroxyethyl)-6-(2-oxo-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-8-yl)oxyhexanamide;

(±)-decahydroquinolinyl-6-(2-oxo-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-8-yl)oxyhexanamide;

N-diphenylmethyl-N-methyl-6-(2-oxo-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-8-yl)oxyhexanamide;

N-phenyl-N-(2-hydroxyethyl)-6-(2-oxo-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-8-yl)oxyhexanamide;

N-phenyl-N-hexyl-6-(2-oxo-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-8-yl)oxyhexanamide;

N-(4-chlorobenzyl)-N-(2-hydroxyethyl)-6-(2-oxo-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-8-yl)oxyhexanamide;

N-cyclohexyl-N-(6-hydroxyhexyl)-6-(2-oxo-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-8-yl)oxyhexanamide;

N-cyclohexyl-N-(2-hydroxyethyl)-6-(2-oxo-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-9-yl)oxyhexanamide;

N-cyclopentyl-N-(2-hydroxyethyl)-6-(2-oxo-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-9-yl)oxyhexanamide;

N-phenyl-N-methyl-6-(2-oxo-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-9-yl)oxyhexanamide;

N-cyclohexylbutyl-N-(2-hydroxyethyl)-6-(2-oxo-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-9-yl)oxyhexanamide;

N-cyclohexyl-N-methyl-6-(2-oxo-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-9-yl)oxyhexanamide;

N-benzyl-N-methyl-6-(2-oxy-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-9-yl)oxyhexanamide;

N-cyclopentyl-N-(2-hydroxyethyl)-6-(2-oxy-6-methyl-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-9-yl)oxyhexanamide;

N-cyclohexyl-N-(6-hydroxyhexyl)-6-(2-oxo-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-9-yl)oxyhexanamide;

N-phenyl-N-(2-hydroxyethyl)-6-(2-oxo-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-9-yl)oxyhexanamide;and

(±)-decahydroquinolinyl-N-methyl-4-(2-oxo-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-9-yl)oxyhexanamide.

EXAMPLE 3

To a solution ofN-cyclohexyl-N-methyl-4-(3-formyl-4-nitrophenyl)oxybutyramide (25 mmol),D-serine methyl ester hydrochloride (7.0 g, 50 mmol) and 3 A molecularsieves (5.0 g) in methanol (75 ml) was added D-serine methyl ester (20.6g, 200 ml). After allowing the solution to stir for 5 minutes at roomtemperature, sodium cyanoborohydride (0.95 g, 15 mmol) was added in oneamount. The reaction mixture was allowed to stir at room temperature for3-4 hours. The reaction solution was then filtered to removeprecipitated solids and molecular sieves, and the methanol was removedby evaporation. The residue was dissolved in ethyl acetate (300 ml) andwas washed with 2N sodium hydroxide (2×100 ml) in brine (2×100 ml). Theorganic extract was dried, filtered and evaporated to give a thicksyrup. The thick syrupy residue was dissolved in absolute ethanol (100ml) and hydrogenated over 10% Pd-C (1.0 g) until uptake of hydrogenceased, approximately 4 hours. The catalyst was removed by filtrationthrough a pad of Celite, and pad was washed clean with absolute ethanol(50 ml). The combined filtrates from the previous paragraph were treatedwith cyanogn bromide (3.20 g, 30 mmol), and the resulting solutionmaintained at a reflux for 16 hours. Upon cooling, the ethanol wasremoved, and the residue was dissolved in ethanol (100 ml) and treatedwith 6N sodium hydroxide (5 ml, 30 mmol) and stirred for 2 hours at roomtemperature. The product precipitated from this mixture and it wasfurther purified by filtration and a water wash and dried, yieldingN-cyclohexyl-N-methyl-4-(2-oxo-3-D-hydroxymethyl-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-7-yl)oxybutyramide,m.p. 218°-219° C.

Proceeding in a like manner but substituting D-serine methyl ester withother appropriate optically active aminocarboxylic acid esters, theremay be prepared the following exemplary optical isomers of Formula I:

N-cyclohexyl-N-methyl-4-(2-oxo-3-L-hydroxymethyl-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-7-yl)oxybutyramide,m.p. 219°-220° C.;

N-cyclohexyl-N-methyl-4-(2-oxo-3-L-methyl-1,2,3,5-tetrahydroimidazo[2,1-b]quinzolin-7-yl)oxybutyramide,m.p. 119°-120° C.;

N-cyclohexyl-N-methyl-4-(2-oxo-3-D-methyl-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-7-yl)oxybutyramide,m.p. 120°-121° C.;

N-cyclohexyl-N-methyl-4-(2-oxo-3-D-ethyl-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-7-yl)oxybutyramide,m.p. 185°-186° C.;

N-cyclohexyl-N-methyl-4-(2-oxo-3-L-ethyl-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-7)oxybutyramide,m.p. 184°-185° C.;

N-cyclohexyl-N-methyl-4-(2-oxo-3-D-(1-hydroxyethyl)-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-7-yl)oxybutyramide,m.p. 211°-212° C.;

N-cyclohexyl-N-methyl-4-(2-oxo-3-L-(1-hydroxyethyl)-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-7-yl)oxybutyramide,m.p. 210°-211° C.;

N-cyclohexyl-N-methyl-4-(2-oxo-3-D-isopropyl-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-7-yl)oxybutyramide,m.p. 178°-179° C.;

N-cyclohexyl-N-methyl-4-(2-oxo-3-D-methylthioethyl-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-7-yl)oxybutyramide;

N-cyclohexyl-N-methyl-4-(2-oxo-3-L-methylthioethyl-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-7-yl)oxybutyramide;

N-cyclohexyl-N-methyl-4-(2-oxo-3-L-isopropyl-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-7-yl)oxybutyramide,m.p. 176°-177° C.;

N-cyclohexyl-N-methyl-4-(2-oxo-3-D-benzyl-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-7-yl)oxybutyramide,m.p. 228°-229° C.;

N-cyclohexyl-N-methyl-4-(2-oxo-3-L-benzyl-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-7-yl)oxybutyramide,m.p. 228°-229° C.;

N-cyclohexyl-N-methyl-4-(2-oxo-3-D-phenyl-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-7-yl)oxybutyramide,m.p. 201°-202° C.;

N-cyclohexyl-N-methyl-4-(2-oxo-3-L-phenyl-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-7-yl)oxybutyramide,m.p. 201°-202° C.;

N-cyclohexyl-N-methyl-4-(2-oxo-3-D-acetoxymethyl-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-7-yl)oxybutyramide;

N-cyclohexyl-N-methyl-4-(2-oxo-3-L-acetoxymethyl-1,2,3,5-tetrahydroimidazo[2,1-b]quinzolin-7-yl)oxybutyramide;

N-cyclohexyl-N-methyl-4-(2-oxo-3-D-carbamoylmethyl-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-7-yl)oxybutyramide;

N-cyclohexyl-N-methyl-4-(2-oxo-3-L-carbamoylmethyl-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-7-yl)oxybutyramide;

N-cyclohexyl-N-methyl-4-(2-oxo-3-D-methoxycarbamoylmethyl-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-7-yl)oxybutyramide;

N-cyclohexyl-N-methyl-4-(2-oxo-3-L-methoxycarbamoylmethyl-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-7-yl)oxybutyramide.

N-cyclohexyl-N-methyl-4-(2-oxo-3-D-pentoxycarbamoylmethyl-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-7-yl)oxybutyramide;and

N-cyclohexyl-N-methyl-4-(2-oxo-3-L-pentoxycarbamoylmethyl-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-7-yl)oxybutyramide.

EXAMPLE 4

Preparation ofN-cyclohexyl-N-methyl-4-(2,5-dioxo-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-7-yl)oxybutyramideand related compounds.

To a suspension of 5-(N-cyclohexyl-N-methylbutyramid-4-yl)oxyanthranilicacid (0.05 g, 1.5 mmol) in ethanol (10 ml) was added an ethanolicsolution of freshly prepared 2-methylthiohydantoin (3.4 mmol). The darkmixture was heated and maintained at reflux for 3 hours. The reactionmixture was then cooled, diluted with water and triturated to giveN-cyclohexyl-N-methyl-4-(2,5-dioxo-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-7-yl)oxybutyramide,m.p. 200°-202° C.

Proceeding in a similar manner, but substituting the appropriateanthranilic acid from Preparation 9 for5-(N-cyclohexyl-N-methylbutyramid-4-yl)oxyanthranilic acid there isprepared the following exemplary compounds:

N-cyclohexyl-N-(2-hydroxyethyl)-4-(2,5-dioxo-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-7-yl)oxybutyramide;

N-cyclohexylmethyl-N-(2-hydroxyethyl)-4-(2,5-dioxo-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-7-yl)oxybutyramide;

N-phenyl-N-methyl-4-(2,5-dioxo-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-7-yl)oxybutyramide;

N-cyclohexylmethyl-N-(2-hydroxyethyl)-4-(2,5-dioxo-5-methyl-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-7-yl)oxybutyramide;

N-phenyl-N-methyl-4-(2,5-dioxo-3-methyl-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-7-yl)oxybutyramide;

N-cyclohexyl-N-(2-hydroxyethyl)-4-(2,5-dioxo-6-chloro-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-7-yl)oxybutyramide;

N-cyclohexylmethyl-N-(2-hydroxyethyl)-4-(2,5-dioxo-3-ethyl-6-chloro-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-6-yl)oxybutyramide;

N-cyclohexyl-N-(2-hydroxyethyl)-4-(2,5-dioxo-9-methyl-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-7-yl)oxybutyramide;

N-cyclohexyl-N-methyl-4-(2,5-dioxo-9-chloro-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-7-yl)oxybutyramide;

N-benzyl-N-methyl-4-(2,5-dioxo-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-7-yl)oxybutyramide;

N,N-dibenzyl-4-(2,5-dioxo-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-7-yl)oxybutyramide;

N,N-dicyclohexyl-4-(2,5-dioxo-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-7-yl)oxybutyramide;

morpholinyl-4-(2,5-dioxo-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-7-yl)oxybutyramide;

N-cyclohexylbutyl-N-(2-hydroxyethyl)-4-(2,5-dioxo-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-7-yl)oxybutyramide;

piperidinyl-4-(2,5-dioxo-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-7-yl)oxybutyramide;

pyrrolidinyl-4-(2,5-dioxo-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-7-yl)oxybutyramide;

N-cyclopentyl-N-(2-hydroxyethyl)-4-(2,5-dioxo-6-chloro-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-7-yl)oxybutyramide;

N-cyclopentylmethyl-N-(2-hydroxyethyl)-4-(2,5-dioxo-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-7-yl)oxybutyramide;

N-methylpiperazinyl-4-(2,5-dioxo-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-7-yl)oxybutyramide;

tetrahydroquinolinyl-4-(2,5-dioxo-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-7-yl)oxybutyramide;

tetrahydroisoquinolinyl-4-(2,5-dioxo-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-7-yl)oxybutyramide;

indolinyl-4-(2,5-dioxo-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-7-yl)oxybutyramide;

(±)-decahydroquinolinyl-4-(2,5-dioxo-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-7-yl)oxybutyramide;

N-diphenylmethyl-N-methyl-4-(2,5-dioxo-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-7-yl)oxybutyramide;

N,N-dimethyl-4-(2,5-dioxo-9-methyl-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-7-yl)oxybutyramide;

N-methyl-N-n-hexyl-4-(2,5-dioxo-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-7-yl)oxybutyramide;

N,N-di-n-hexyl-4-(2,5-dioxo-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-7-yl)oxybutyramide;

N-n-hexyl-N-(2-hydroxyethyl)-4-(2,5-dioxo-1,2,3,5-tetrahydroimidazo-[2,1-b]quinazolin-7-yl)oxybutyramide;

N,N-di(2-hydroxyethyl)-4-(2,5-dioxo-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-7-yl)oxybutyramide;

N-phenyl-N-(2-hydroxyethyl)-4-(2,5-dioxo-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-7-yl)oxybutyramide;

N-phenyl-N-n-hexyl-4-(2,5-dioxo-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-7-yl)oxybutyramide;

N-benzyl-N-methyl-4-(2,5-dioxo-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-7-yl)oxybutyramide;

N-phenethyl-N-(2-hydroxyethyl)-4-(2,5-dioxo-1,2,3,5-tetra-hydroimidazo-[2,1-b]quinazolin-7-yl)oxybutyramide;

N-benzyl-N-(2-hydroxyethyl)-4-(2,5-dioxo-1,2,3,5-tetrahydroimidazo-[2,1-]quinazolin-7-yl)oxybutyramide;

N-(4-chlorobenzyl)-N-methyl-4-(2,5-dioxo-1,2,3,5-tetrahydroimidazo-[2,1-b]quinazolin-7-yl)oxybutyramide;

N-(4-methoxybenzyl)-N-methyl-4-(2,5-dioxo-1,2,3,5-tetrahydroimidazo-[2,1-b]quinazolin-7-yl)oxybutyramide;

N-cyclohexyl-N-(6-hydroxyhexyl)-4-(2,5-dioxo-1,2,3,5-tetrahydroimidazo-[2,1-b]quinazolin-7-yl)oxybutyramide;

N-cyclohexyl-N-(2-hydroxyethyl)-4-(2,5-dioxo-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-6-yl)oxybutyramide;

N-cyclohexyl-N-(2-hydroxyethyl)-4-(2,5-dioxo-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-6-yl)oxybutyramide;

N-cyclohexylbutyl-N-(2-hydroxyethyl)-4-(2,5-dioxo-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-6-yl)oxybutyramide;

N-phenyl-N-methyl-4-(2,5-dioxo-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-6-yl)oxybutyramide;

N-cyclohexyl-N-(2-hydroxyethyl)-4-(2,5-dioxo-7-chloro-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-6-yl)oxybutyramide;

N-cyclohexyl-N-(2-hydroxyethyl)-4-(2,5-dioxo-7-methyl-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-6-yl)oxybutyramide;

N-cyclohexyl-N-methyl-4-(2,5-dioxo-9-chloro-1,2,3,5-tetra-hydroimidazo[2,1-b]quinazolin-6-yl)oxybutyramide;

N-cyclohexyl-N-methyl-4-(2,5-dioxo-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-8-yl)oxybutyramide;

N-cyclohexyl-N-methyl-4-(2,5-dioxo-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-8-yl)oxybutyramide;

N-cyclohexyl-N-methyl-4-(2,5-dioxo-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-8-yl)oxybutyramide;

N-cyclohexyl-N-(2-hydroxyethyl)-4-(2,5-dioxo-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-8-yl)oxybutyramide;

N-cyclohexyl-N-(2-hydroxyethyl)-4-(2,5-dioxo-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-9-yl)oxybutyramide;

N-cyclohexylmethyl-N-(2-hydroxyethyl)-4-(2,5-dioxo-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-8-yl)oxybutyramide;

N-cyclohexylbutyl-N-(2-hydroxyethyl)-4-(2,5-dioxo-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-8-yl)oxybutyramide;

N-cyclohexylmethyl-N-(2-hydroxyethyl)-4-(2,5-dioxo-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-9-yl)oxybutyramide;

N-n-hexyl-N-(2-hydroxyethyl)-4-(2,5-dioxo-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-8-yl)oxybutyramide;

N-cyclohexylmethyl-N-(2-hydroxyethyl)-4-(2,5-dioxo-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-9-yl)oxybutyramide;

N-cyclohexylbutyl-N-(2-hydroxyethyl)-4-(2,5-dioxo-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-9-yl)oxybutyramide;

N-cyclohexylbutyl-N-(6-hydroxyhexyl)-4-(2,5-dioxo-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-9-yl)oxybutyramide;

N-cyclopentyl-N-(2-hydroxyethyl)-7-(2,5-dioxo-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-7-yl)oxyheptanamide;

N-cyclohexyl-N-(2-hydroxyethyl)-7-(2,5-dioxo-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-7-yl)oxyheptanamide;

N-cyclohexyl-N-methyl-7-(2,5-dioxo-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-7-yl)oxyheptanamide;

N-cyclopentyl-N-methyl-7-(2,5-dioxo-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-7-yl)oxyheptanamide;

N-cyclohexyl-N-(2-hydroxyethyl)-7-(2,5-dioxo-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-6-yl)oxyheptanamide;

N-cyclohexyl-N-(2-hydroxyethyl)-7-(2,5-dioxo-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-8-yl)oxyheptanamide;

N-cyclohexyl-N-(2-hydroxyethyl)-7-(2,5-dioxo-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-9-yl)oxyheptanamide;

(±)-decahydroquinolinyl-7-(2,5-dioxo-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-7-yl)oxyheptanamide;

N-cyclopentyl-N-(2-hyroxyethyl)-5-(2,5-dioxo-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-7-yl)oxypentamide;

N-cyclopentyl-N-(2-hydroxyethyl)-5-(2,5dioxo-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-7-yl)oxypentamide;

N-cyclohexylbutyl-N-(2-hydroxyethyl)-5-(2,5-dioxo-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-7-yl)oxypentamamide;

N-cyclohexyl-N-methyl-5-(2,5-dioxo-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-7-yl)oxypentamide;

N-cyclopentyl-N-methyl-5-(2,5-dioxo-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-7-yl)oxypentamide;

N-cyclohexyl-N-(2-hydroxyethyl)-5-(2,5-dioxo-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-6-yl)oxypentanamide;

N-cyclopentyl-N-methyl-5-(2,5-dioxo-6-methyl-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-7-yl)oxypentanamide;

N-cyclohexyl-N-(2-hydroxyethyl)-5-(2,5-dioxo-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-8-yl)oxypentamide;

N-cyclohexyl-N-(2-hydroxyethyl)-5-(2,5-dioxo-6-chloro-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-8-yl)oxypentanamide;

N-cyclohexyl-N-(2-hydroxyethyl)-5-(2,5-dioxo-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-9-yl)oxypentamide;

(±)-decahydroquinolinyl-5-(2,5-dioxo-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-7-yl)oxypentamide;

(±)-decahydroquinolinyl-5-(2,5-dioxo-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-6-yl)oxypentanamide;

(±)-decahydroquinolinyl-5-(2,5-dioxo-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-8-yl)oxypentanamide;

N-cyclopentyl-N-(2-hydroxyethyl)-6-(2,5-dioxo-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-7-yl)oxyhexanamide;

N-pentyl-N-(2-hydroxyethyl)-6-(2,5-dioxo-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-7-yl)oxyhexanamide;

N-cyclohexylbutyl-N-(2-hydroxyethyl)-6-(2,5-dioxo-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-7-yl)oxyhexanamide;

N-cyclohexyl-N-methyl-6-(2,5-dioxo-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-7-yl)oxyhexanamide;

N-cyclopentylmethyl-N-methyl-6-(2,5-dioxo-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-7-yl)oxyhexanamide;

N-cyclohexyl-N-(2-hydroxyethyl)-6-(2,5-dioxo-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-6-yl)oxyhexanamide;

N-cyclopentyl-N-methyl-6-(2,5-dioxo-6-methyl-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-7-yl)oxyhexanamide;

N-cyclohexyl-N-(2-hydroxyethyl)-6-(2,5-dioxo-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-8-yl)oxyhexanamide;

N-cyclohexylbutyl-N-(2-hydroxyethyl)-6-(2,5-dioxo-6-chloro-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-8-yl)oxyhexanamide;

N-phenyl-N-(2-hydroxyethyl)-6-(2,5-dioxo-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-7-yl)oxyhexanamide;

(±)-decahydroquinolinyl-6-(2,5-dioxo-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-7-yl)oxyhexanamide;

(±)-decahydroquinolinyl-6-(2,5-dioxo-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-6-yl)oxyhexanamide;and

(±)-decahydroquinolinyl-6-(2,5-dioxo-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-8-yl)oxyhexanamide.

EXAMPLE 5

The formation ofN-cyclohexyl-N-(acetoxyethyl)-4-(2-oxo-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-7-yl)oxybutyramideand analogues thereof, where A or R₂ in Formula I contans a hydroxyalkylgroup, is carried out by treating the compound with an acid anhydride inpyridine.

Proceeding in a similar manner, but substituting the appropriateN-hydroxyalkyl compound from Example 2 forN-cyclohexyl-N-(acetoxyethyl)-4-(2-oxo-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-7-yl)oybutyramide,all N-hydroxyalkyl-substituted compounds may be converted to theircorresponding acylate, exemplified by the following compounds:

N-cyclohexyl-N-(acetoxyethyl)-4-(2-oxo-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-7-yl)oxybutyramide,m.p. 164°-166° C.;

N-cyclohexyl-N-(isopropionyloxyethyl)-4-(2-oxo-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-7-yl)oxybutyramide,m.p. 154°-155° C.;

N-cyclohexyl-N-(butyryloxyethyl)-4-(2-oxo-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-7-yl)oxybutyramide,m.p. 152°-153° C.;

N-cyclohexyl-N-(4-acetoxybutyl)-4-(2-oxo-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-7-yl)oxybutyramide;

N-cyclopentyl-N-(acetoxyethyl)-4-(2-oxo-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-7-yl)oxybutyramide;

N-cyclohexyl-N-(6-acetoxyhexyl)-4-(2-oxo-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-7-yl)oxybutyramide;

N-cyclohexyl-N-(formyloxyethyl)-4-(2-oxo-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-7-yl)oxybutyramide;

N-cyclohexyl-N-(hexanyloxyethyl)-4-(2-oxo-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-7-yl)oxybutyramide;

N-cyclohexyl-N-(6-benzoyloxyhexyl)-4-(2-oxo-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-7-yl)oxybutyramide;

N-cyclohexyl-N-(benzoyloxyethyl)-4-(2-oxo-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-7-yl)oxybutyramide,m.p. 94°-95° C.;

N-benzyl-N-(acetoxyethyl)-4-(2-oxo-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-7-yl)oxybutyramide;

N-cyclohexylbutyl-N-(formyloxyethyl)-4-(2-oxo-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-7-yl)oxybutyramide;

N-cyclopentylpropyl-N-(acetoxyethyl)-4-(2-oxo-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-7-yl)oxybutyramide;

N-hexyl-N-(3-acetoxypropyl)-4-(2-oxo-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-7-yl)oxybutyramide;

N-phenyl-N-(acetoxyethyl)-4-(2-oxo-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-7-yl)oxybutyramide;

N-cyclohexyl-N-(acetoxyethyl)-5-(2-oxo-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-7-yl)oxypentanamide;

N-cyclohexyl-N-(acetoxyethyl)-5-(2-oxo-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-7-yl)oxypentanamide;

N-cyclohexyl-N-(6-acetoxyhexyl)-5-(2-oxo-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-7-yl)oxypentanamide;

N-cyclopentyl-N-(acetoxyethyl)-5-(2-oxo-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-7-yl)oxypentanamide;

N-cyclohexyl-N-(6-benzoyloxyhexyl)-5-(2-oxo-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-7-yl)oxypentanamide;

N-cyclohexyl-N-(butyryloxyethyl)-5-(2-oxo-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-7-yl)oxypentanamide;

N-cyclohexyl-N-(3-acetoxypropyl)-5-(2-oxo-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-7-yl)oxypentanamide;

N-cyclopentyl-N-(benzoyloxyethyl)-5-(2-oxo-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-7-yl)oxypentanamide;

N-benzyl-N-(acetoxyethyl)-5-(2-oxo-2-oxo-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-7-yl)oxypentanamide;

N-cyclohexylbutyl-N-(acetoxyethyl)-5-(2-oxo-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-7-yl)oxypentanamide;

N-cyclopentylpropyl-N-(acetoxyethyl)-5-(2-oxo-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-7-yl)oxypentanamide;

N-hexyl-N-(3-acetoxypropyl)-5-(2-oxo-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-7-yl)oxypentanamide;

N-phenyl-N-(benzoyloxyethyl)-5-(2-oxo-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-7-yl)oxypentanamide;

N-cyclohexyl-N-(acetoxyethyl)-7-(2-oxo-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-7-yl)oxyheptanamide;

N-cyclohexyl-N-(3-acetoxypropyl)-7-(2-oxo-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-7-yl)oxyheptanamide;

N-cyclohexyl-N-(6-acetoxyhexyl)-7-(2-oxo-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-7-yl)oxyheptanamide;

N-cyclopentyl-N-(acetoxyethyl)-7-(2-oxo-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-7-yl)oxyheptanamide;

N-cyclohexyl-N-(6-benzoyloxyhexyl)-7-(2-oxo-1,2,3,5-tetrahyroimidazo[2,1-b]quinazolin-7-yl)oxyheptanamide;

N-cyclohexylmethyl-N-(acetoxyethyl)-7-(2-oxo-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-7-yl)oxyheptanamide;

N-cyclopentyl-N-(acetoxyethyl)-7-(2-oxo-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-7-yl)oxyheptanamide;

N-benzyl-N-(acetoxyethyl)-7-(2-oxo-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-7-yl)oxyheptanamide;

N-cyclohexylbutyl-N-(3-acetoxypropyl)-7-(2-oxo-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-7-yl)oxyheptanamide;

N-cyclopentylehtyl-N-(acetoxyethyl)-7-(2-oxo-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-7-yl)oxyheptanamide;

N-hexyl-N-(acetoxypropyl)-7-(2-oxo-1,2,3,5-tetrahydroimidazo[2,1-]quinazolin-7-yl)oxyheptanamide;

N-phenyl-N-(acetoxyethyl)-7-(2-oxo-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-7-yl)oxyheptanamide;

N-cyclohexyl-N-(acetoxyethyl)-1-(2-oxo-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-7-yl)oxyacetamide;

N-cyclohexyl-N-(6-acetoxyhexyl)-1-(2-oxo-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-7-yl)oxyacetamide;

N-cyclohexyl-N-(benzoyloxyethyl)-1-(2-oxo-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-7-yl)oxyacetamide;

N-cyclopentyl-N-(acetoxyethyl)-1-(2-oxo-1,2,3,5-tetrahydromidazo[2,1-b]quinazolin-7-yl)oxyacetamide;

N-cyclohexylmethyl-N-(acetoxyhexyl)-1-(2-oxo-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-7-yl)oxyacetamide;

N-cyclohexyl-N-(6-benzoyloxyhexyl)-6-(2-oxo-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-7-yl)oxyhexanamide;

N-cyclopentyl-N-(acetoxyethyl)-6-(2-oxo-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-7-yl)oxyhexanamide;

N-hexyl-N-(acetoxyethyl)-6-(2-oxo-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-7-yl)oxyhexanamide;and

N-cyclohexyl-N-(acetoxypropyl)-6-(2-oxo-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-7-yl)oxyhexanamide.

EXAMPLE 6N-Cyclohexyl-N-methyl-4-(2-oxo,1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-7-yl)oxybutyramide

To a solution of4-(2-oxo-1,2,3,5-tetrahydroimadazo[2,1-b]quinazolin-7-yl)oxybutyric acid(3.44 g) and 1-hydroxybenzotriazole (1.5 g) in 25 ml drydimethylformamide was added diisopropylcarbodiimide (1.39 g). After onehour at room temperature, a solution of N-methylcyclohexylamine (1.56ml) and 1.32 ml of N-methylmorpholine in 10 ml of dry dimethylformamidewas added. The resulting solution was stirred overnight at roomtemperature and was then diluted with water. The resulting precipitatewas collected and dried over phosphorous pentoxide to giveN-cyclohexyl-N-methyl-4-(2-oxo-1,2,3,5-tetrahydroimadazo[2,1-b]quinazolin-7-yl)oxybutyramide.

Proceeding in a similar manner, all oxyalkyl acids prepared as perPreparation 10 may be converted to their corresponding amide.

EXAMPLE 7

Ethylene glycol (50 ml) was saturated with ammonia gas at 0° C., and toit was added the ethyl ester described in Preparation 9 (3.2 g). Thesuspension was heated in a steel pressure apparatus for 3 days at 200°C. Upon cooling, the precipitate was collected by filtration, washedwith ethanol and dried to yield the unsubstituted(2-oxo-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-7-yl)oxybutyramide,m.p. 280°-282° C.

By using similar conditions with other primary amines, the correspondingprimary amides can be prepared:

N-cyclohexyl-4-(2-oxo-1,2,3,5-tetrahydroimidazo-[2,1-b]quinazolin-7-yl)oxybutyramide,m.p. 255°-256° C.;

N-methyl-4-(2-oxo-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-7-yl)oxybutyramide;

N-ethyl-4-(2-oxo-1,2,3,5-tetrahydroimidazo-[2,1-b]quinazolin-7-yl)oxybutyramide.

EXAMPLE 8

Into a solution of the ethyl ester (3.2 g, 10 mmol) prepared fromPreparation 9 and tetra-N-butylammonium bromide (6.44 g, 20 mmol) in DMF(100 ml) was added aqueous KOH (1.5 g in 5 ml H₂ O), stirred overnightat room temperature. Molecular sieves (3 Å, 25 g ) were added, and themixture was left to stand 3 days. N-methylcyclohexylamine (2.6 ml, 20mmol) and bis(o-nitrophenyl)phenylphosphonate (10 g, 25 mmol) wereadded, and the mixture was shaken for 24 hours. The mixture was filteredthrough Celite, and the DMF was evaporated at high vacuum. The residuewas triturated with 5% aqueous ammonium hydroxide and ethanol (1:1) togive a precipitate, collected by filtration, washed with ethanol anddried to giveN-cyclohexyl-N-methyl-4-(2-oxo-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-7-yl)oxybutyramide,m.p. 243°-244° C.

EXAMPLE 9

The compounds of Formula I wherein R₄ is hydrogen are converted to thosewherein R₄ is alkyl of 1 to 6 carbon atoms, benzyl or hydroxy loweralkyl by the following procedure.

To a solution ofN-cyclohexyl-N-methyl-4-(2-oxo-1,2,3,5-tetrahydroimadazo[2,1-b]quinazolin-7-yl)-oxybutyramidein dry dimethylformamide was added sodium hydride (1.05 equivalents).The mixture was stirred at 60° C. for 30 minutes to give a homogeneoussolution. 1-bromobutane (1.1 equivalents) was added via a syringe afterwhich the mixture was stirred at 60° C. for 2 hours. The solvent wasevaporated and the residue taken up in ethyl acetate which was washedwith saturated brine, dried and filtered. Evaporation of the solventaffordedN-cyclohexyl-N-methyl-4-(1-butyl-2-oxo-1,2,3,5-tetrahydroimadazo[2,1-b]quinazolin-7-yl)oxybutyramide.

EXAMPLE 10 Conversion of Free Base to Salt

A two-fold stoichiometric excess of 3% hydrogen chloride in methanol isadded to a solution of 1.0 g. ofN-cyclohexyl-N-methyl-4-(2-oxo-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-7-yl)oxybutyramidein 20 ml methanol. Diethyl ether is added until precipitation iscomplete. The product is filtered, washed with ether, air dried andrecrystallized to giveN-cyclohexyl-N-methyl-4-(2-oxo-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-7-yl)oxybutyramidehydrochloride, m.p. -232°-234° C.

In a similar manner, all compounds of Formula I in free base form may beconverted to the acid addition salt by treatment with hydrogen chlorideor another pharmaceutically acceptable acid addition salt-forming acidsuch as exemplified herein earlier.

EXAMPLE 11 Conversion of Salt to Free Base

1.0 g ofN-cyclohexyl-N-methyl-4-(2-oxo-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-7-yl)oxybutyramideHCl suspended in 50 ml of ether is stirred with a twofold stoichiometricexcess of dilute aqueous potassium carbonate solution until the salt iscompletely dissolved. The organic layer is then separated, washed twicewith water, dried over magnesium sulfate and evaporated to yieldN-cyclohexyl-N-methyl-4-(2-oxo-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-7-yl)oxybutyramideas the free base.

EXAMPLE 12 Direct interchange of acid addition salts

N,N-dibenzyl-4-(2-oxo-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-7-yl)oxybutyramideacetate (1.0 g) is dissolved in 50 ml water containing a stoichiometricequivalent of sulfuric acid, and the solution evaporated to dryness. Theproduct is suspended in ethanol and filtered, air dried andrecrystallized from methanol/acetone to yieldN,N-dibenzyl-4-(2-oxo-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-7-yl)oxybutyramidesulfate.

EXAMPLE 13

Compounds of the present invention, either the free base or apharmaceutically acceptable acid addition salt, may be orallyadministered to a subject as a tablet. While the active ingredient maycomprise anywhere between 1 and 99 percent of the formulation thatpercentage preferably will be an amount which will cause to be deliveredto the subject, the active ingredient in an amount of between 20 mg and100 mg per tablet. Following is a representative tablet formulation inwhich the active ingredient isN-cyclehexyl-N-methyl-4-(2-oxo-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-7-yl)oxybutyramide.However, the formulation profile given below may be used to formulate atablet for any of the compounds represented by Formula I.

    ______________________________________                                                         Quantity per                                                 Ingredients      tablet, mgs.                                                 ______________________________________                                        Active ingredient                                                                              25                                                           cornstarch       20                                                           lactose, spray-dried                                                                           153                                                          magnesium stearate                                                                              2                                                           ______________________________________                                    

The above ingredients are thoroughly mixed and pressed into singlescored tablets.

EXAMPLE 14

An alternative oral dosage form is to fill hard shell gelatin capsuleswith a powder containing the active ingredient in the desired amount.Using the active ingredient mentioned in Example 6 above, the acidaddition salts, or any other compound according to Formula I there maybe prepared an exemplary hard shell gelatin capsule formulation usingthe following ingredients

    ______________________________________                                                         Quantity per                                                 Ingredients      tablet, mgs.                                                 ______________________________________                                        Active ingredient                                                                              100                                                          lactose, spray-dried                                                                           148                                                          magnesium stearate                                                                              2                                                           ______________________________________                                    

The above ingredients are mixed and introduced into a hard-shell gelatincapsule.

EXAMPLE 15

Alternatively, compounds of the present invention may be prepared as asuspension for oral administration. Any of the compounds of Formula I,either in free lance form or as the acid addition salt, may be used inthis formulation.

An oral suspension is prepared having the following composition:

    ______________________________________                                        Ingredients                                                                   ______________________________________                                        Active ingredient     0.1       g                                             fumaric acid          0.5       g                                             sodium chloride       2.0       g                                             methyl paraben        0.1       g                                             granulated sugar      25.5      g                                             sorbitol (70% solution)                                                                             12.85     g                                             Veegum K (Vanderbilt Co.)                                                                           1.0       g                                             flavoring             0.035     ml                                            colorings             0.5       mg                                            distilled water       q.s. to 100                                                                             ml                                            ______________________________________                                    

EXAMPLE 16 Acute and delayed toxicity ofN-cyclohexyl-N-methyl-4-(2-oxo-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-7-yl)oxybutyramide

Three groups of three male mice (Sim:(ICR)f_(BR)) in a weight range of20 to 24 grams were used in this study.N-cyclohexyl-N-methyl-4-(2-oxo-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-7-yl)oxy-butyramidewas administered intraperitoneally as an aqueous suspension (polysorbate80). The mice were observed for acute and delayed lethality:

    ______________________________________                                               Dose     Death                                                         ______________________________________                                               1,500 mg/Kg                                                                            0/3                                                                  1,000 mg/Kg                                                                            0/3                                                                    500 mg/Kg                                                                            0/3                                                           ______________________________________                                    

The results indicate that the LD₅₀ (intraperitoneal) ofN-cyclohexyl-N-methyl-4-(2-oxo-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-7-yl)oxy-butyramideis >1500 mg/Kg. When the test compound was administered orally, also asan aqueous suspension (polysorbate 80), the results are as follows:

    ______________________________________                                               Dose     Death                                                         ______________________________________                                               1,500 mg/Kg                                                                            0/3                                                                  1,000 mg/Kg                                                                            0/3                                                                    500 mg/Kg                                                                            0/3                                                           ______________________________________                                    

The LD₅₀ (oral) ofN-cyclohexyl-N-methyl-4-(2-oxo-1,2,3,5-tetrahydroimidazo-[2,1-b]quinazolin-7-yl)oxybutyramideis also >1500 mg/Kg.

EXAMPLE 17

Cyclic AMP phosphodiesterase activity and inhibition of plateletaggregation were determined as follows.

Cyclic AMP phosphodiesterase assay

The inhibition of cyclic AMP phosphodiesterase activity by the subjectcompounds was assayed by the method of Filburn and Karn, Analyt.Biochem., 52:505-516 (1973), using 1 μM cyclic AMP as the substrate.Human platelet cyclic AMP phosphodiesterase was obtained from humandonors. Platelets were isolated and washed by centrifugation, themembranes ruptured by a sequential freeze-thaw procedure and hypotoniclysis and the soluble enzyme isolated by high speed centrifugation. Theenzyme was stored in aliquots at -20° C.

Platelet Aggregation

Blood was collected into evacuated tubes containing sodium citrate (30mM). Platelet rich plasma was collected after centrifugation.Aggregation was followed by a turbidimetric procedure described by G. V.R. Born, J. Physiol., Lond., 162:67P-68P (1962).

Inhibition of cyclic AMP phosphodiesterase data (relative totheophylline) are presented in Table I below. This table contains theIC₅₀ values for human platelet phosphodiesterase and IC₂₅ values for ratheart phosphodiesterase.

                  TABLE I                                                         ______________________________________                                        INHIBITION OF CYCLIC AMP PHOSPHODIESTERASE                                    IN HUMAN PLATELETS AND RAT HEART                                                                           Rat     Rela-                                    Compound.sup.c     Human     Heart   tive                                                         Posi-  Platelet                                                                              IC.sub.25                                                                           Poten-                               A             n     tion.sup.b                                                                           IC.sub.50 [nM]                                                                        [nM]  cy.sup.a                             ______________________________________                                        N--methyl-    3     7      12.5    260   21,600                               N--cyclohexyl                                                                 N--hydroxyethyl-                                                                            3     7      12.5    70    21,600                               N--cyclohexyl                                                                 N--methyl-    3     7      26.0    350   10,400                               N--phenyl                                                                     N--methyl-    3     7      26.0    240   10,400                               N--benzyl                                                                     N,N--dibenzyl 3     7      9.2     60    29,300                               N--methyl-    3     7      15.0    60    18,000                               N--diphenylmethyl                                                             N,N--dicyclohexyl                                                                           3     7      1.4     16    186,000                              morpholinyl   3     7      1600    7,000 169                                  piperidinyl   3     7      260     1,500 1,040                                pyrollidinyl  3     7      340     1,700 794                                  tetrahydro-   3     7      10.0    160   27,000                               quinolinyl                                                                    tetrahydroiso-                                                                              3     7      180     520   1,500                                quinolinyl                                                                    indolinyl     3     7      76      260   3,550                                (±)-decahydro-                                                                           3     7      13.5    200   20,000                               quindinyl                                                                     perhexylenyl  3     7      1.8     36    146,000                              N--methyl-    1     7      820     4,400 330                                  N--cyclohexyl                                                                 N--methyl-    4     7      4.6     22    58,700                               N--cyclohexyl                                                                 N--methyl-    5     7      12.0    21    22,500                               N--cyclohexyl                                                                 N--methyl-    6     7      16.0    45    16,800                               N--cyclohexyl                                                                 N--methyl-    3     6      2,000   --    135                                  N--cyclohexyl                                                                 N--methyl-    3     8      150     --    1,800                                N--cyclohexyl                                                                 N--methyl-    3     9      >10.sup.4                                                                             --    <2.7                                 N--cyclohexyl                                                                 N--ethylacetate                                                                             3     7      1.4     --    193,000                              N--cyclohexyl-                                                                N--ethylisobutrate                                                                          3     7      1.1     --    245,000                              N--cyclohexyl                                                                 N--ethylpivalate                                                                            3     7      1.0     --    270,000                              N--cyclohexyl                                                                 N--ethylbenzoate                                                                            3     7      0.94    --    287,000                              N--cyclohexyl                                                                 N--ethyl      3     7      1.5     <10   180,000                              N--cyclohexyl                                                                 N--isopropyl  3     7      3.2     15    84,000                               N--cyclohexyl                                                                 N--(2-methoxyethyl)                                                                         3     7      1.3     <10   208,000                              N--cyclohexyl                                                                 N--cyclohexyl 3     7      72      180   38,000                               N--2-morpholinylethyl                                                                       3     7      4.1     32    66,000                               N--cyclohexyl                                                                 N--methyl-    3     7      1.0     <10   270,000                              N--cycloheptyl                                                                Optical Isomers.sup.d                                                         N--cyclohexyl 3     7      27.5    90    9,800                                N--methyl                                                                     3-L-hydroxymethyl                                                             N--cyclohexyl 3     7      18.5    72    14,600                               N--methyl                                                                     3-D-hydroxymethyl                                                             N--cyclohexyl 3     7      5.4     27    50,000                               N--methyl                                                                     3-D-methyl                                                                    ______________________________________                                         .sup.a Potency relative to theophylline which is assigned a value of 1 on     human platelet phosphodiesterase.                                             .sup.b Position of oxyalkylamide side chain on the ring.                      .sup.c Formula I wherein Y, R.sub.1, R.sub.2, R.sub.3 and R.sub.4 are all     hydrogen.                                                                     .sup.d Formula I wherein Y, R.sub.1, R.sub.2, and R.sub.4 are all             hydrogen.                                                                

EXAMPLE 18 Inotropic Activity of the Compounds of the present Invention

Mongrel dogs were anesthetized intravenously with 35 mg/Kg sodiumpentobarbital and supplemented as needed. Blood pressure was measuredwith a Statham pressure transducer via a cannula inserted from a femoralartery into the abdominal aorta. Heart rate was recorded by acardiotachometer from a lead II electrocardiogram. Right ventricularcontractile force was recorded from a Walton-Brodie strain gauge suturedto the right ventricle following a midsternal thoracotomy. A Harvardrespirator was used to ventilate the dogs with room air through anendotracheal tube. The dog was bilaterally vagotomized. Following amidline laparotomy, a cannula was sutured into the duodenum forintraduodenal administration of test compound. A femoral vein wascannulated for administration of isoproterenol. All data were recordedon a Beckman R611 Dynograph.

To assess the responsiveness of each dog, isoproterenol was givenintravenously at half-log interval doses from 0.007 to 2.1 or 6.67μg/Kg. The test compound was then administered intraduodenally, usuallyat a low dose of 2 mg/Kg and subsequently at higher doses of 6.32 and/or20 mg/Kg, if necessary. In a few instances, some compounds administeredintraduodenally at dose levels from 0.316 to 3.16 mg/Kg.

The test results are summarized in the following Table:

                  TABLE II                                                        ______________________________________                                                         Peak Effects as % of                                                          Max. Isoproterenol                                                                  Rt.                                                                           Ventricular     Blood                                                dose     Contractile                                                                             Heart Pres-                                  Compound      (mg/kg)  Force     Rate  sure                                   ______________________________________                                        N--cyclohexyl-N--                                                                           2        48        30    25                                     methyl-4-(2-oxo-1,2,3,5-                                                                    6.23     44        40    96                                     tetrahydroimidazo-                                                            [2,1-b]quinazolin-7-yl]-                                                      oxybutyramide                                                                 N--cyclohexyl-N--                                                                           0.316    23        11    17                                     methyl-4-(2-oxo-3-L-                                                                        1.0      69        44    54                                     methyl-1,2,3,5-tetrahy-                                                                     3.16     55        58    94                                     droimidazo[2,1-b]quina-                                                                     0.1 (i.v.)                                                                             32        55    97                                     zolin-7-yl)oxybu-                                                             tryamide                                                                      N--cyclohexyl-N--                                                                           0.316    18        18    13                                     methyl-4-(2-oxo-3-D-                                                                        1.0      50        48    49                                     methyl-1,2,3,5-tetrahy-                                                                     3.16     53        72    82                                     droimidazo[2,1-b]quina-                                                                     0.1 (i.v.)                                                                             43        73    82                                     zolin-7-yl)oxybu-                                                             tyramide                                                                      ______________________________________                                    

EXAMPLE 19 Antimetastatic activity against Lewis Lung Carcinoma(Spontaneous Metastases)

Mice (female, C57B1/6, 16-18 gm) were inoculated subcutaneously betweenthe inguinal and axillary areas with 0.2 ml of a freshly prepared tumorbrei. Mice were treated orally with control vehicle (0.5%carboxymethylcellulose (CMC) or with test compound in suspension in 0.5%CMC. Treatments were initiated one day after tumor implantation, andcontinued every other day throughout the experiment. 20-21 days afterinitial implantation of the tumor, mice were sacrificed, weight of theprimary tumor was determined, and the number of lung metastases wasdetermined by counting under a disecting microscope. The results areshown in Table III.

                  TABLE III                                                       ______________________________________                                                                     Pulmonary                                                     Size of Primary Tumor                                                                         Metastases                                       Treatment    (gm ± S.E.)  Median                                           ______________________________________                                        Control      5.1 ± 0.4    28                                               N--cyclohexyl-N--                                                                          3.9 ± 0.4*   10.5*                                            methyl-4-(2-oxo-                                                              1,2,3,5-tetrahydro-                                                           imidazo[2,1-b]-                                                               quinazolin-7-yl)-                                                             oxybutyramide                                                                 (5 mg/kg)                                                                     ______________________________________                                         *p < 0.05                                                                

EXAMPLE 20 Antimetastatic activity against B-16 Melanoma

Mice (female, C57B1/6, 16-18 gm) were injected intravenously with either7.5×10⁴ viable B16-BL6 or B16-F10 melanoma cells, as indicated. The micewere orally treated with vehicle or drug, starting one day after tumorcell injection, and continuing every other day until the mice weresacrificed 20-21 days after tumor cell inoculation. The number of lungmetastases was determined as described above, and the results are shownin Table IV (B16-BL6) or Table V (B16-F10).

                  TABLE IV                                                        ______________________________________                                        Effect of N--cyclohexyl-N--methyl-                                            4-(2-oxo-1,2,3,5-tetrahydroimidazo[2,1-b]-                                    quinazalin-7-yl)oxybutyramide                                                 on Experimental Metastases from B16-BL6 Melanoma                                             Pulmonary Metastases                                           Treatment      Median                                                         ______________________________________                                        Control        10                                                             N--cyclohexyl-N--                                                                             3*                                                            methyl-4-(2-oxo-                                                              1,2,3,5-tetrahydro-                                                           imidazo[2,1-b]-                                                               quinazolin-7-yl)-                                                             oxybutyramide                                                                 (5 mg/kg)                                                                     ______________________________________                                         *p ≦ 0.02                                                         

                  TABLE V                                                         ______________________________________                                        Effect of N--cyclohexyl-N--methyl-                                            4-(2-oxo-1,2,3,5-tetrahydroimidazo[2,1-b]-                                    quinazolin-7-yl)oxybutyramide                                                 on Experimental Metastases from B16-F10 Melanoma                                             Pulmonary Metastases                                           Treatment      Median                                                         ______________________________________                                        Control        23                                                             N--cyclohexyl-N--                                                                            1.5**                                                          methyl-4-(2-oxo-                                                              1,2,3,5-tetrahydro-                                                           imidazo[2,1-b]-                                                               quinazolin-7-yl)-                                                             oxybutyramide                                                                 (5 mg/kg)                                                                     ______________________________________                                         **p ≦ 0.01                                                        

What is claimed is:
 1. A compound according to the formula ##STR8## oran optical isomer thereof or a pharmaceutically acceptable acid additionsalt thereof, wherein:n is an integer of 1 to 6; R₁ is hydrogen or alkylof 1 to 4 carbons; R₂ is hydrogen or R₁ and R₂ are combined to form anoxo group; R₃ is hydrogen, alkyl of 1 to 6 carbons, phenyl, benzyl,hydroxy lower alkyl or an aliphatic acylate thereof of 1 to 6 carbonatoms or an aryl acylate thereof of 7 to 12 carbon atoms, carbamoylalkyl, carboxyalkyl, alkoxycarbonylalkyl or an α-amino acid side chain;R₄ is hydrogen, alkyl of 1 to 6 carbons, benzyl, or hydroxy lower alkyl;Y is hydrogen, alkyl of 1 to 4 carbon atoms, halo or lower alkoxy; A isNR₅ R₆ wherein R₅ an R₆ are independently selected from the groupconsisting of: hydrogen; alkyl of 1 to 6 carbon atoms; hydroxyalkyl of 1to 6 carbon atoms or an aliphatic acylate thereof of 1 to 6 carbon atomsor an aryl acylate thereof of 7 to 12 carbon atoms; cycloalkyl of 3 to 8carbon atoms or cycloalkyl lower alkyl of 4 to 12 carbon atoms whereinthe cycloalkyl ring is unsubstituted or substituted with a lower alkyl,lower alkoxy, --OH, --OCOR₇, halo, --NH₂, --N(R₇)₂, --NHCOR₇, --COOH, or--COO(R₇) group wherein R₇ is lower alkyl; phenyl or phenyl lower alkylwherein phenyl is unsubstituted or substituted with at least one loweralkyl, halo or lower alkoxy group or an --NH₂, --N(R₇)₂, --NHCOR₇,--COOH, or --COOR₇ group wherein R₇ is lower alkyl; or wherein N, R₅ andR₆ are combined to form a selected from the group consisting ofmorpholinyl, piperidinyl, perhexylenyl, N-loweralkylpiperazinyl,pyrrolidinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl,(±)-decahydroquinolinyl, and indolinyl.
 2. A compound according to theformula ##STR9## or an optical isomer thereof or a pharmaceuticallyacceptable acid addition salt thereof, wherein:n is an integer of 1 to6; R₁ is hydrogen or alkyl of 1 to 4 carbons; R₂ is hydrogen or R₁ andR₂ are combined to form an oxo group; R₃ is an aliphatic hydroxy loweralkyl acylate of 1 to 6 carbon atoms or an aryl hydroxy lower alkylacylate of 7 to 12 carbon atoms, carbamoyl alkyl, carboxyalkyl,alkoxycarbonylalkyl or an α-amino acid side chain; R₄ is hydrogen, alkylof 1 to 6 carbons, benzyl, or hydroxy lower alkyl; Y is hydrogen, alkylof 1 to 4 carbon atoms, halo or lower alkoxy; A is NR₅ R₆ wherein R₅ andR₆ are independently selected from the group consisting of: hydrogen;alkyl of 1 to 6 carbon atoms; hydroxyalkyl of 1 to 6 carbon atoms or analiphatic acylate thereof of 1 to 6 carbon atoms or an aryl acylatethereof of 7 to 12 carbon atoms; cycloalkyl of 3 to 8 carbon atoms orcycloalkyl lower alkyl of 4 to 12 carbon atoms wherein the cycloalkylring is unsubstituted or substituted with a lower alkyl, lower alkoxy,--OH, --OCOR₇, halo, --NH₂, --N(R₇)₂, --NHCOR₇, --COOH, or --COO(R₇)group wherein R₇ is lower alkyl; and phenyl or phenyl lower alkylwherein phenyl is unsubstituted or substituted with 1 or more loweralkyl, halo or lower alkoxy groups or an --NH₂, --N(R₇)₂, --NHCOR₇,--COOH, or --COOR₇ group wherein R₇ is lower alkyl; or where N, R₅ andR₆ together form a group selected from the group consisting ofmorpholinyl, piperidinyl, perhexylenyl, N-loweralkylpiperazinyl,pyrrolidinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl,(±)-decahydroquinolinyl, and indolinyl.
 3. A compound according to theformula ##STR10## or an optical isomer thereof or a pharmaceuticallyacceptable acid addition salt thereof, wherein:n is 3 or 4; R₄ ishydrogen or methyl; Y is hydrogen, alkyl of 1 to 4 carbon atoms, halo orlower alkoxy; A is NR₅ R₆ wherein the nitrogen substituents areindependently selected from the group consisting of: hydrogen; alkyl of1 to 6 carbon atoms; hydroxyalkyl of 1 to 6 carbon atoms or an aliphaticacylate thereof of 1 to 6 carbon atoms or an aryl acylate thereof of 7to 12 carbon atoms; cycloalkyl of 3 to 8 carbon atoms or cycloalkyllower alkyl of 4 to 12 carbon atoms wherein the cycloalkyl ring isunsubstituted or substituted with a lower alkyl, lower alkoxy, --OH,--OCOR₇, halo, --NH₂, --N(R₇)₂, --NHCOR₇, --COOH, or --COO(R₇) groupwherein R₇ is lower alkyl; phenyl or phenyl lower alkyl wherein phenylis unsubstituted or substituted with at least one lower alkyl, halo orlower alkoxy group or an --NH₂, --N(R₇)₂, --NHCOR₇, --COOH, or --COOR₇group wherein R₇ is lower alkyl; or N, R₅, and R₆ together form a groupselected from the group consisting of morpholinyl, piperidinyl,perhexylenyl, N-loweralkylpiperazinyl, pyrrolidinyl,tetrahydroquinolinyl, tetrahydroisoquinolinyl, (±)-decahydroquinolinyl,and indolinyl.
 4. A compound according to claim 3 wherein R₄ ishydrogen; and wherein the R₅ and R₆ substituents are independentlyselected from the group consisting of: alkyl of 1 to 6 carbon atoms;hydroxyalkyl of 1 to 6 carbon atoms or an aliphatic acylate thereof of 1to 6 carbon atoms or an aryl acylate thereof of 7 to 12 carbon atoms;and cycloalkyl of 3 to 8 carbon atoms or cycloalkyl lower alkyl of 4 to12 carbon atoms.
 5. A compound according to claim 3 wherein n is 3; andwherein R₅ is alkyl of 1 to 6 carbon atoms and R₆ is cycloalkyl of 3 to8 carbon atoms.
 6. The compound of claim 5 which isN-cyclohexyl-N-methyl-4-(2-oxo-1,2,3,5-tetrahydroimidazo-[2,1-b]quinazolin-9-yl)oxybutyramideor a pharmaceutically acceptable addition salt thereof.
 7. The compoundof claim 5 which isN-cyclohexyl-N-methyl-4-(2-oxo-1,2,3,5-tetrahydroimidazo-[2,1-b]quinazolin-8-yl)oxybutyramideor a pharmaceutically acceptable addition salt thereof.
 8. The compoundof claim 5 which isN-cyclohexyl-N-methyl-4-(2-oxo-1,2,3,5-tetrahydroimidazo-[2,1-b]quinazolin-6-yl)oxybutyramideor a pharmaceutically acceptable addition salt thereof.
 9. The compoundof claim 5 which isN-cyclooctyl-N-methyl-4-(2-oxo-1,2,3,5-tetrahydroimidazo-[2,1-b]quinazolin-7-yl)oxybutyramideor a pharmaceutically acceptable addition salt thereof.
 10. The compoundof claim 5 which isN-cyclopentyl-N-methyl-4-(2-oxo-1,2,3,5-tetrahydroimidazo-[2,1-b]quinazolin-7-yl)oxybutyramideor a pharmaceutically acceptable addition salt thereof.
 11. The compoundof claim 5 which isN-cyclohexyl-N-ethyl-4-(2-oxo-1,2,3,5-tetrahydroimidazo-[2,1-b]quinazolin-7-yl)oxybutyramideor a pharmaceutically acceptable addition salt thereof.
 12. The compoundof claim 5 which isN-cyclohexyl-N-isopropyl-4-(2-oxo-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-7-yl)oxybutyramideor a pharmaceutically acceptable addition salt thereof.
 13. The compoundof claim 5 which isN-cyclohexyl-N-2-methoxyethyl-4-(2-oxo-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-7-yl)oxybutyramideor a pharmaceutically acceptable addition salt thereof.
 14. The compoundof claim 5 which isN-cyclohexyl-N-n-butyl-4-(2-oxo-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-7-yl)oxybutyramideor a pharmaceutically acceptable addition salt thereof.
 15. The compoundof claim 5 which isN-cycloheptyl-N-methyl-4-(2-oxo-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-7-yl)oxybutyramideor a pharmaceutically acceptable addition salt thereof.
 16. A compoundaccording to claim 4 wherein n is 3; and wherein the R₅ and R₆substitutents are independently selected from the group consisting of:hydroxyalkyl of 1 to 6 carbon atoms or an aliphatic acylate thereof of 1to 6 carbon atoms or an aryl acylate thereof of 7 to 12 carbon atoms;cycloalkyl of 3 to 8 carbon atoms; and cycloalkyl lower alkyl of 4 to 12carbon atoms.
 17. The compound of claim 16 which isN-cyclohexyl-N-t-butyryloxyethyl-4-(2-oxo-1,2,3,5-tetra-hydroimidazo[2,1-b]quinazolin-7-yl)oxybutyramideor a pharmaceutically acceptable acid addition salt thereof.
 18. Thecompound of claim 16 which isN-cyclohexyl-N-isopropionyloxyethyl-4-(2-oxo-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-7-yl)oxybutyramideor a pharmaceutically acceptable acid addition salt thereof.
 19. Acompound according to the formula ##STR11## or an optical isomer thereofor a pharmaceutically acceptable acid addition salt thereof, wherein:R₃is hydrogen, alkyl of 1 to 6 carbons, phenyl, benzyl, hydroxy loweralkyl or an aliphatic acylate thereof of 1 to 6 carbon atoms or an arylacylate thereof of 7 to 12 carbon atoms, carbamoyl alkyl, carboxyalkyl,alkoxycarbonylalkyl or an α-amino acid side chain; A is NR₅ R₆ whereinthe nitrogen is substituted with alkyl of 1 to 6 carbon atoms andcycloalkyl of 3 to 8 carbon atoms.
 20. The compound of claim 19 which isN-cyclohexyl-N-methyl-4-(2-oxo-3-D-hydroxymethyl-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-7-yl)oxybutyramideor a pharmaceutically acceptable addition salt thereof.
 21. The compoundof claim 19 which isN-cyclohexyl-N-methyl-4-(2-oxo-3-L-hydroxymethyl-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-7-yl)oxybutyramideor a pharmaceutically acceptable addition salt thereof.
 22. The compoundof claim 19 which isN-cyclohexyl-N-methyl-4-(2-oxo-3-D-methyl-1,2,3,5-tetra-hydroimidazo[2,1-b]quinazolin-7-yl)oxybutyramideor a pharmaceutically acceptable addition salt thereof.
 23. The compoundof claim 19 which isN-cyclohexyl-N-methyl-4-(2-oxo-3-L-methyl-1,2,3,5-tetra-hydroimidazo[2,1-b]quinazolin-7-yl)oxybutyramideor a pharmaceutically acceptable addition salt thereof.
 24. The compoundof claim 19 which isN-cyclohexyl-N-methyl-4-(2-oxo-3-D-ethyl-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-7-yl)oxybutyramideor a pharmaceutically acceptable addition salt thereof.
 25. The compoundof claim 19 which isN-cyclohexyl-N-methyl-4-(2-oxo-3-L-ethyl-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-7-yl)oxybutyramideor a pharmaceutically acceptable addition salt thereof.
 26. The compoundof claim 19 which isN-cyclohexyl-N-methyl-4-(2-oxo-3-D-(1-hydroxyethyl)-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-7-yl)oxybutyramideor a pharmaceutically acceptable addition salt thereof.
 27. The compoundof claim 19 which isN-cyclohexyl-N-methyl-4-(2-oxo-3-L-(1-hydroxyethyl)-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-7-yl)oxybutyramideor a pharmaceutically acceptable addition salt thereof.
 28. The compoundof claim 19 which isN-cyclohexyl-N-methyl-4-(2-oxo-3-D-isopropyl-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-7-yl)oxybutyramideor a pharmaceutically acceptable addition salt thereof.
 29. The compoundof claim 19 which isN-cyclohexyl-N-methyl-4-(2-oxo-3-L-isopropyl-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-7-yl)oxybutyramideor a pharmaceutically acceptable addition salt thereof.
 30. The compoundof claim 19 which isN-cyclohexyl-N-methyl-4-(2-oxo-3-D-benzyl-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-7-yl)oxybutyramideor a pharmaceutically acceptable addition salt thereof.
 31. The compoundof claim 19 which isN-cyclohexyl-N-methyl-4-(2-oxo-3-L-benzyl-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-7-yl)oxybutyramideor a pharmaceutically acceptable addition salt thereof.
 32. The compoundof claim 19 which isN-cyclohexyl-N-methyl-4-(2-oxo-3-D-phenyl-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-7-yl)oxybutyramideor a pharmaceutically acceptable addition salt thereof.
 33. The compoundof claim 19 which isN-cyclohexyl-N-methyl-4-(2-oxo-3-L-phenyl-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-7-yl)oxybutyramideor a pharmaceutically acceptable addition salt thereof.
 34. A compoundaccording to claim 3, wherein n is
 4. 35. The compound of claim 34 whichisN-cyclohexyl-N-methyl-5-(2-oxo-1,2,3,5-tetrahydroimidazo-[2,1-b]quinazolin-7-yl)oxypentamideor a pharmaceutically acceptable acid addition salt thereof.
 36. Acompound according to claim 3, wherein R₄ is hydrogen; n is 3; andwherein R₅ and R₆ are independently selected from the group consistingof: alkyl of 1 to 6 carbon atoms; phenyl; and phenyl lower alkyl. 37.The compound of claim 36 which isN-diphenylmethyl-N-methyl-4-(2-oxo-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-7-yl)oxybutyramideor a pharmaceutically acceptable acid addition salt thereof.
 38. Thecompound of claim 36 which isN,N-dibenzyl-4-(2-oxo-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-7-yl)oxybutyramideor a pharmaceutically acceptable acid addition salt thereof.
 39. Thecompound of claim 36 which isN-benzyl-N-methyl-4-(2-oxo-1,2,3,5-tetrahydro-imidazo[2,1-b]quinazolin-7-yl)oxybutyramideor a pharmaceutically acceptable acid addition salt thereof.
 40. Thecompound of claim 36 which isN-phenyl-N-methyl-4-(2-oxo-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-7-yl)oxybutyramideor a pharmaceutically acceptable acid addition salt thereof.
 41. Thecompound according to claim 1 wherein n is 1; Y, R₁, R₂, R₃ and R₄ areall hydrogen; and wherein R₅ is alkyl of 1 to 6 carbon atoms and R₆ iscycloalkyl of 3 to 8 carbon atoms.
 42. The compound of claim 41 which isN-cyclohexyl-N-methyl-2-(2oxo-1,2,3,5-tetrahydroimidazo-[2,1-b]quinazolin-7-yl)oxyacetamideor a pharmaceutically acceptable acid addition salt thereof.
 43. Acompound according to claim 1 wherein n is 5; Y, R₁, R₂, R₃ and R₄ areall hydrogen; and R₅ and R₆ are independently alkyl of 1 to 6 carbonatoms or cycloalkyl of 3 to 8 carbon atoms.
 44. The compound of claim 43which isN-cyclohexyl-N-methyl-6-(2-oxo-1,2,3,5-tetrahydroimidazo-[2,1-b]quinazolin-7-yl)oxyhexanamideor a pharmaceutically acceptable acid addition salt thereof.
 45. Acompound according to claim 1, wherein n is 6; Y, R₁, R₂, R₃ and R₄ areall hydrogen; and R₅ and R₆ are independently alkyl of 1 to 6 carbonatoms or cycloalkyl of 3 to 8 carbon atoms.
 46. The compound of claim 45which isN-cyclohexyl-N-methyl-7-(2-oxo-1,2,3,5-tetrahydroimidazo-[2,1-b]quinazolin-7-yl)oxyheptanamideor a pharmaceutically acceptable acid addition salt thereof.
 47. Acompound according to claim 1, wherein n is 3; Y, R₁, R₂, R₃, R₄, and R₅are all hydrogen; and R₆ is a cycloalkyl group of 3 to 8 carbon atoms.48. The compound of claim 47 which isN-cyclohexyl-4-(2-oxo-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-7-yl)oxybutyramideor a pharmaceutically acceptable acid addition salt thereof.
 49. Acompound according to claim 1, wherein n is 3; and Y, R₁, R₂, R₃, R₄, R₅and R₆ are all hydrogen; or a pharmaceutically acceptable acid additionsalt thereof.
 50. A compound according to claim 1, wherein n is 3; R₁and R₂ are combined to form an oxo group; and Y, R₃ and R₄ are hydrogen.51. The compound of claim 50 which isN-cyclohexyl-N-methyl-4-(2,5-dioxo-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-7-yl)oxybutyramideor a pharmaceutically acceptable acid addition salt thereof.
 52. Acompound according to claim 1, wherein n is 3; Y, R₁, R₂, R₃ and R₄ areall hydrogen; and A is tetrahydroquinolinyl or a pharmaceuticallyacceptable acid addition salt thereof.
 53. A compound according to claim1, wherein n is 3; Y, R₁, R₂, R₃ and R₄ are all hydrogen; and A isperhexylenyl or a pharmaceutically acceptable acid addition saltthereof.
 54. A compound according to claim 1, wherein n is 3; Y, R₁, R₂,R₃ and R₄ are all hydrogen; and A is indolinyl or a pharmaceuticallyacceptable acid addition salt thereof.
 55. A compound according to claim1, wherein n is 3; Y, R₁, R₂, R₃ and R₄ are all hydrogen; and A ispiperidinyl or a pharmaceutically acceptable acid addition salt thereof.56. A compound according to claim 1, wherein n is 3; Y, R₁, R₂, R₃ andR₄ are all hydrogen; and A is pyrrolidinyl or a pharmaceuticallyacceptable acid addition salt thereof.
 57. A compound according to claim1, wherein n is 3; Y, R₁, R₂, R₃ and R₄ are all hydrogen; and A is(±)-decahydroquinolinyl or a pharmaceutically acceptable acid additionsalt thereof.
 58. A compound according to claim 1, wherein n is 3; Y,R₁, R₂, R₃ and R₄ are all hydrogen; and A is tetrahydroisoquinolinyl, ora pharmaceutically acceptable acid addition salt thereof.
 59. A compoundaccording to claim 1, wherein n is 3; Y, R₁, R₂, R₃ and R₄ are allhydrogen; and A is morpholinyl, or a pharmaceutically acceptable acidaddition salt thereof.
 60. A compound according to claim 1, wherein n is3; Y, R₁, R₂, R₃ and R₄ are all hydrogen; R₅ is cyclohexyl; and R₆ is2-morpholinylethyl; or a pharmaceutically acceptable acid addition saltthereof.
 61. A pharmaceutical composition comprising a pharmaceuticallyacceptable excipient and a therapeutically effective amount of acompound of the formula ##STR12## or an optical isomer thereof or apharmaceutically acceptable acid addition salt thereof whereinn is aninteger of 1 to 6; R₁ is hydrogen or alkyl of 1 to 4 carbons; R₂ ishydrogen or R₁ and R₂ are combined to form an oxo group; R₃ is hydrogen,alkyl of 1 to 6 carbons, phenyl, benzyl, hydroxy lower alkyl or analiphatic acylate thereof of 1 to 6 carbon atoms or an aryl acylatethereof of 7 to 12 carbon atoms, carbamoyl alkyl, carboxyalkyl,alkoxycarbonylalkyl or an α-amino acid side chain; R₄ is hydrogen,benzyl, hydroxy lower alkyl or alkyl of 1 to 6 carbons; Y is hydrogen,alkyl of 1 to 4 carbon atoms, halo or lower alkoxy; A is NR₅ R₆ whereinR₅ and R₆ are independently selected from the group consisting of:hydrogen; alkyl of 1 to 6 carbon atoms; hydroxyalkyl of 1 to 6 carbonatoms or an aliphatic acylate thereof of 1 to 6 carbon atoms or an arylacylate thereof of 7 to 12 carbon atoms; cycloalkyl of 3 to 8 carbonatoms or cycloalkyl lower alkyl of 4 to 12 carbon atoms wherein thecycloalkyl ring is unsubstituted or substituted with a lower alkyl,lower alkoxy, --OH, --OCOR₇, halo, --NH₂, --N(R₇)₂, --NHCOR₇, --COOH, or--COO(R₇) group wherein R₇ is lower alkyl; and phenyl or phenyl loweralkyl wherein phenyl is unsubstituted or substituted with 1 or morelower alkyl, halo or lower alkoxy groups or an --NH₂, --N(R₇)₂,--NHCOR₇, --COOH, or --COOR₇ group wherein R₇ is lower alkyl; or whereinN, R₅ and R₆ are combined to form a group selected from the groupconsisting of morpholinyl, piperidinyl, perhexylenyl,N-loweralkylpiperazinyl, pyrrolidinyl, tetrahydroquinolinyl,tetrahydroisoquinolinyl, (±)-decahydroquinolinyl and indolinyl.
 62. Apharmaceutical composition comprising a pharmaceutically acceptableexcipient and a therapeutically effective amount of a compound of theformula ##STR13## or an optical isomer thereof or a pharmaceuticallyacceptable acid addition salt thereof whereinn is an integer of 1 to 6;R₁ is hydrogen or alkyl of 1 to 4 carbons; R₂ is hydrogen or R₁ and R₂are combined to form an oxo group; R₃ is an aliphatic hydroxy loweralkyl acylate of 1 to 6 carbon atoms or an aryl hydroxy lower alkylacylate of 7 to 12 carbon atoms, carbamoyl alkyl, carboxyalkyl,alkoxycarbonylalkyl or an α-amino acid side chain; R₄ is hydrogen,benzyl, hydroxy lower alkyl or alkyl of 1 to 6 carbons; Y is hydrogen,alkyl of 1 to 4 carbon atoms, halo or lower alkoxy; A is NR₅ R₆ whereinR₅ and R₆ are independently selected from the group consisting of:hydrogen; alkyl of 1 to 6 carbon atoms; hydroxyalkyl of 1 to 6 carbonatoms or an aliphatic acylate of 1 to 6 carbon atoms or an aryl acylateof 7 to 12 carbon atoms; cycloalkyl of 3 to 8 carbon atoms or cycloalkyllower alkyl of 4 to 12 carbon atoms wherein the cycloalkyl ring isunsubstituted or substituted with a lower alkyl, lower alkoxy, --OH,--OCOR₇, halo, --NH₂, --N(R₇)₂, --NHCOR₇, --COOH, or --COO(R₇) groupwherein R₇ is lower alkyl; phenyl or phenyl lower alkyl wherein phenylis unsubstituted or substituted with 1 or more lower alkyl, halo orlower alkoxy groups or an --NH₂, --N(R₇)₂, --NHCOR₇, --COOH, or --COOR₇group wherein R₇ is lower alkyl; or wherein R₅ and R₆ are combined toform a group selected from the group consisting of morpholinyl,piperidinyl, perhexylenyl, N-loweralkylpiperazinyl, pyrrolidinyl,tetrahydroquinolinyl, tetrahydroisoquinolinyl, (±)-decahydroquinolinyl,and indolinyl.
 63. A method for inhibiting 3',5'-cyclic AMPphosphodiesterase which method comprises administering a cyclic AMPphosphodiesterase inhibiting amount of a compound of the formula##STR14## or an optical isomers thereof or a pharmaceutically acceptableacid addition salt thereof either alone or in admixture with a apharmaceutically acceptable excipient whereinn is an integer of 1 to 6;R₁ is hydrogen or alkyl of 1 to 4 carbons; R₂ is hydrogen or R₁ and R₂are combined to form an oxo group; R₃ is hydrogen, alkyl of 1 to 6carbons, phenyl, benzyl, hydroxy lower alkyl or an aliphatic acylatethereof of 1 to 6 carbon atoms or an aryl acylate thereof of 7 to 12carbon atoms, carbamoyl alkyl, carboxyalkyl, alkoxycarbonylalkyl or anα-amino acid side chain; R₄ is hydrogen, benzyl, hydroxy lower alkyl oralkyl of 1 to 6 carbons; Y is hydrogen, alkyl of 1 to 4 carbon atoms,halo or lower alkoxy; A is NR₅ R₆ wherein R₅ and R₆ are independentlyselected from the group consisting of: hydrogen; alkyl of 1 to 6 carbonatoms; hydroxyalkyl of 1 to 6 carbon atoms or an aliphatic acylate of 1to 6 carbon atoms or an aryl acylate of 7 to 12 carbon atoms; cycloalkylof 3 to 8 carbon atoms or cycloalkyl lower alkyl of 4 to 12 carbon atomswherein the cycloalkyl ring is unsubstituted or substituted with a loweralkyl, lower alkoxy, --OH, --OCOR₇, halo, --NH₂, --N(R₇)₂, --NHCOR₇,--COOH, or --COO(R₇) group wherein R₇ is lower alkyl; phenyl or phenyllower alkyl wherein phenyl is unsubstituted or substituted with 1 ormore lower alkyl, halo or lower alkoxy groups or an --NH₂, --N(R₇)₂,--NHCOR₇, --COOH, or --COOR₇ group wherein R₇ is lower alkyl; or whereinN, R₅ and R₆ are combined to form a group selected from the groupconsisting of morpholinyl, piperidinyl, perhexylenyl,N-loweralkylpiperazinyl, pyrrolidinyl, tetrahydroquinolinyl,tetrahydroisoquinolinyl, (±)-decahydroquinolinyl, and indolinyl.
 64. Amethod of inhibiting 3',5'-cyclic AMP phosphodiesterase which methodcomprises administering a cyclic AMP phosphodiesterase inhibiting amountof a compound of the formula ##STR15## or an optical isomer thereof or apharmaceutically acceptable acid addition salt thereof either alone orin admixture with a a pharmaceutically acceptable excipient whereinn isan integer of 1 to 6; R₁ is hydrogen or alkyl of 1 to 4 carbons; R₂ ishydrogen or R₁ and R₂ are combined to form an oxo group; R₃ is hydrogen,alkyl of 1 to 6 carbons, phenyl, benzyl, hydroxy lower alkyl or analiphatic acylate thereof of 1 to 6 carbon atoms or an aryl acylatethereof of 7 to 12 carbon atoms, carbamoyl alkyl, carboxyalkyl,alkoxycarbonylalkyl or an α-amino acid side chain; R₄ is hydrogen,benzyl, hydroxy lower alkyl or alkyl of 1 to 6 carbons; Y is hydrogen,alkyl of 1 to 4 carbon atoms, halo or lower alkoxy; A is NR₅ R₆ whereinR₅ and R₆ are independently selected from the group consisting of:hydrogen; alkyl of 1 to 6 carbon atoms; hydroxyalkyl of 1 to 6 carbonatoms or an aliphatic acylate of 1 to 6 carbon atoms or an aryl acylateof 7 to 12 carbon atoms; cycloalkyl of 3 to 8 carbon atoms or cycloalkyllower alkyl of 4 to 12 carbon atoms wherein the cycloalkyl ring isunsubstituted or substituted with a lower alkyl, lower alkoxy, --OH,--OCOR₇, halo, --NH₂, --N(R₇)₂, --NHCOR₇, --COOH, or --COO(R₇) groupwherein R₇ is lower alkyl; phenyl or phenyl lower alkyl wherein phenylis unsubstituted or substituted with 1 or more lower alkyl, halo orlower alkoxy groups or an --NH₂, --N(R₇)₂, --NHCOR₇, --COOH, or --COOR₇group wherein R₇ is lower alkyl; or wherein N, R₅ and R₆ are combined toform a group selected from the group consisting of morpholinyl,piperidinyl, perhexylenyl, N-loweralkylpiperazinyl, pyrrolidinyl,tetrahydroquinolinyl, tetrahydroisoquinolinyl, (±)-decahydroquinolinyl,and indolinyl.
 65. A method for inhibiting tumor growth in cases ofspontaneous metastases or melanoma which method comprises administeringto a subject in need of such treatment a therapeutically effectiveamount of a compound of the formula ##STR16## or an optical isomerthereof or a pharmaceutically acceptable acid addition salt thereofeither alone or in admixture with a a pharmaceutically acceptableexcipient whereinn is an integer of 1 to 6; R₁ is hydrogen or alkyl of 1to 4 carbons; R₂ is hydrogen or R₁ and R₂ are combined to form a oxogroup; R₃ is hydrogen, alkyl of 1 to 6 carbons, phenyl, benzyl, hydroxylower alkyl or an aliphatic acylate thereof of 1 to 6 carbon atoms or anaryl acylate thereof of 7 to 12 carbon atoms, carbamoyl alkyl,carboxyalkyl, alkoxycarbonylalkyl or an α-amino acid side chain; R₄ ishydrogen, benzyl, hydroxy lower alkyl or alkyl of 1 to 6 carbons; Y ishydrogen, alkyl of 1 to 4 carbon atoms, halo or lower alkoxy; A is NR₅R₆ wherein R₅ and R₆ are independently selected from the groupconsisting of: hydrogen; alkyl of 1 to 6 carbon atoms; hydroxyalkyl of 1to 6 carbon atoms or an aliphatic acylate of 1 to 6 carbon atoms or anaryl acylate of 7 to 12 carbon atoms; cycloalkyl of 3 to 8 carbon atomsor cycloalkyl lower alkyl of 4 to 12 carbon atoms wherein the cycloalkylring is unsubstituted or substituted with a lower alkyl, lower alkoxy,--OH, --OCOR₇, halo, --NH₂, --N(R₇)₂, --NHCOR₇, --COOH, or --COO(R₇)group wherein R₇ is lower alkyl; phenyl or phenyl lower alkyl whereinphenyl is unsubstituted or substituted with 1 or more lower alkyl, haloor lower alkoxy groups or an --NH₂, --N(R₇)₂, --NHCOR₇, --COOH, or--COOR₇ group wherein R.sub. 7 is lower alkyl; or wherein N, R₅ and R₆are combined to form a group selected from the group consisting ofmorpholinyl, piperidinyl, perhexylenyl, N-loweralkylpiperazinyl,pyrrolidinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl,(±)-decahydroquinolinyl, and indolinyl.